MXPA01005733A - Compositions and methods for the treatment of anorectal disorders - Google Patents

Abstract

Compositions and methods for the treatment of anorectal disorders are provided in which certain combinations of NO donors, PDE inhibitors, superoxide (O2-) scavengers, b-adrenergic agonists, cAMP-dependent protein kinase activators, a1-adrenergic antagonists, L-type Ca2+ channel blockers, estrogens, ATP-sensitive K+ channel activators and smooth muscle relaxants are used.

Description

COMPOSITIONS AND METHODS FOR THE TREATMENT OF ANORECTAL DISORDERS BACKGROUND OF THE INVENTION This invention is directed to compositions and methods for treating anorectal disorders, such as anal fissure, anal ulcers, haemorrhoidal diseases, spasm of the levator muscle, by administration to the appropriate anal area of a subject (e.g., the internal anal canal), who needs such treatment, of a combination agent agent, that relax the internal anal sphincter muscle. More specifically, this invention describes compositions and methods for treating anorectal disorders with agents that induce an increase in cyclic nucleotides in the anal sphincter muscle or agents that simulate the actions of cyclic nucleotides or reduce intracellular calcium concentrations in tissue. of the affected anal sphincter muscle, thus reducing hypertonicity and / or anal sphincter spasm in patients afflicted with these disorders. In general, anal fissure (fissure in the anus) and ulcers, hemorrhoidal diseases, and elevator spasm (proctalgia fugax) are benign, relatively common conditions of the anorectal area, affecting subjects, which include humans, of all ages, sex races. However, these conditions can be problematic and inconvenient to treat and painful to endure. A fissure or anal ulcer is a tear or ulcer of the mucosa or lining tissue of the distal anal canal. An anal fissure or ulcer may be associated with other systemic or local diseases, but, more frequently, they appear as an isolated finding. The idiopathic fissure or ulcer is confined to the anal mucosa usually found in the posterior midline, distal to the dentate line. An individual with a fissure or anal ulcer, frequently experiences pain and anal bleeding, the pain being most pronounced during and after bowel movements. Hemorrhoids are specialized vascular areas that are placed under the anal mucosa. Symptomatic hemorrhoidal diseases are manifested by bleeding, thrombosis and / or prolapse of the hemorrhoidal tissues. Commonly, internal hemorrhoidal tissues swell in the anal canal during defecation and result in bleeding and pain. As the tissue enlarges, more bleeding, pain, prolapse, and thrombosis may ensue. Thrombosis of hemorrhoids is yet another cause of bleeding and pain.

Elevator spasm is a condition that affects women more frequently than men. This syndrome is characterized by spasticity of the levator ani muscles, a portion of the anal sphincter complex. The patient suffering from the spasm of the elevator can experience a severe episodic rectal pain. A physical exam can reveal spasm of the puborectal muscle and the pain can be reproduced by the direct pressure of this muscle. Bleeding is not normally associated with this condition. The sphincters are circular groups of smooth muscles that control the orifices of the hollow organs. The sphincters present throughout the gastrointestinal tract (Gl) control the passage of materials through this system of the body. When they contract, the sphincters close the holes that lead to the hollow organs, such as the stomach, intestine, anus, etc. In order to open the sphincter, the muscles must relax. The sphincter that closes the anus (anal sphincter) consists of two groups of sphincter muscles. The external anal sphincter is a thin flat muscle of striated muscle fibers, adherent to the integument that surrounds the margin of the anus. The internal anal sphincter (IAS) is a ring of smooth muscles that surround the lower extremity of the rectum and is formed by an aggregate of involuntary smooth muscle fibers. Local inflammation can cause spasm and sphincter pain. The anal sphincter spasm is a condition in which the muscles of the internal anal sphincter are under abnormal tension. Strong contractions of the internal anal sphincter, associated with sphincter spasm, often results in painful linear ulcers or tender fissures, known as rectal fissures, in the margin of the anus, especially after defecation. Spasm of the anal sphincter is also considered a cause of pain, and followed by rectal surgery or hemorrhoids with thrombosis. Current treatments of rectal fissures are aimed at relieving sphincter spasm and include dilation (under anesthesia) or cutting a part of the sphincter (lateral internal sphincterotomy). The applications of heat, cold, amametine water, topical anesthetics, topical steroids, agents for softening the stools and rest in the bed have also been prescribed to treat rectal pain. However, none of these approaches significantly modify the sphincter spasm itself. The treatment of, for example, anal fissures, has not changed significantly for more than 150 years. Typically, non-surgical therapies involve the use of volume laxatives and sitz baths. Approximately 60% of acute anal fissures heal within three weeks under this regimen. The acute anal fissures that heal become anal fissures and chronic anal ulcers The hypertonicity of the internal anal sphincter muscle, which is believed to be the main cause of anal fissures, can be alleviated through the surgical sphincterotomy. The standards of The Standards Task Force of the American Society of Colon and Rectal Surgeons recommend the management of chronic anal fissures by "subcutaneous or open intern lateral sphincterotomy, intern posterior sphincterotomy with advanced fin, or with manual dilation". Healing occurs immediately after sphincterotomy in 95% of cases. This successful sphincterotomy (or anal dilation) is associated with a significant decrease in intra-anal pressure. However, a number of patients experience incontinence following this surgical procedure. A known moderator of sphincter tone is nitric oxide (NO). Nitric oxide has been shown to lead to a concentration-dependent reduction in the latent tension of the smooth muscle strips of the internal sphincter in vi tro (Rattan et al., Am. J. Physiol 262: G107-11 (1992) and NO donors, for example nitroglycerin dinitrate isosorbide, isosorbide mononitrate, reduce anal pressure in man. NO has been shown to intervene in the adapted relaxation of other sphincters in the gastrointestinal tract, which includes the sphincter of the lower esophagus (Conklin et al., Gastroenterology 104: 1439-1444 (1993); Tottrup et al., Br. J. Pharmacol., 104: 113-116 (1991)), pyloric sphincter (Bayguinov et al., Am. J. Physiol. 264: G975-983), sphincter of Oddi (Mourelle et al., Gastroenterology 105: 1299-1305 (1993 )), and the ileocolic sphincter (Ward et al., Br. J. Pharmacol. 105: 776.782 (1992)), It is thought that nitric oxide (NO) or NO-like substances serve as important control mechanisms for the general phenomenon of gastrointestinal adapted relaxation. U.S. Patent No. 5,504,117 and 5,693,676 describe the use of NO donors for the treatment of anorectal conditions. However, the development of adverse side effects, such as the development of headaches, has limited the use of such NO donors as the sole therapy, especially at higher doses. There is clearly a significant need for other non-surgical treatments of anorectal disorders, including, for example, anal fissures and other anorectal conditions, caused by anal sphincter spasm and / or hypertonicity, which include hemorrhoidal diseases and proctalgia fugax .

SUMMARY OF THE INVENTION In one aspect, the present invention provides compositions for the treatment of anorectal disorders, comprising a nitric oxide donor in combination with a second agent (typically one which modulates the levels of cAMP or cGMP). The second agent may be an inhibitor of type V phosphodiesterase (PDEV), a type II phosphodiesterase inhibitor (PDE II), a type IV phosphodiesterase inhibitor (PDE IV), a non-specific PDE inhibitor, a β-adrenergic agonist, a cAMP-dependent protein kinase activator, an estrogen or estrogen-like compound, or an oti-adrenergic antagonist. The agent can also be a superoxide anion scavenger (02 ~) an activator of the ATP-sensitive K + channel, or a smooth muscle relaxant, although these agents do not directly modulate the levels of cAMP or cGMP. The present invention also provides methods of using these compositions. In another aspect, the present invention provides compositions for the treatment of anorectal disorders, comprising a phosphodiesterase inhibitor, preferably a PDE I inhibitor, a PDE IV inhibitor or a PDE V inhibitor, alone or in combination with another agent selected d-adrenergic receptor agonists, ot-adrenergic antagonists, estrogens, Ca2 + d L-type channel blockers, ATP-sensitive K + channel activators, smooth muscle relaxants, in combination with a pharmaceutically acceptable carrier. The present invention also provides methods of using these compositions. In another aspect, the present invention provides compositions for the treatment of anorectal disorders, comprising a β-adrenergic receptor agonist, preferably a β2- or β3-adrenergic receptor agonist, either alone or in combination with another agent, selected from PDE inhibitors that hydrolyze cAMP (for example a PDE IV inhibitor), non-specific PDE inhibitors, ai-adrenergic antagonists, estrogens or estrogen-like compounds, L-type Ca2 + channel blockers, or activators of the K + channel sensitive to ATP, and methods of using these compositions. In yet another aspect, the present invention provides compositions for the treatment of anorectal disorders, comprising an activator of the K + channel, sensitive to ATP, either alone or in combination with another agent, selected from activators of the protein-dependent protein kinase. cAMP, ot -adrenergic antagonists, estrogens, blockers of the L-type Ca2 + channel, or smooth muscle relaxants, and methods of using those compositions. In still another aspect, the present invention provides compositions for the treatment of anorectal disorders, comprising an ot -adrenergic antagonist, either alone or in combination with another agent, selected from PDE inhibitors that hydrolyze cAMP (preferably an inhibitor of the PDE IV), or the agents that relax the smooth muscles, and methods to use those compositions. In another aspect, the present invention provides compositions for the treatment of anorectal disorders, comprising protein kinase activators, dependent on cyclic nucleotides, either alone or in combination with another agent. Methods for the use of these compositions are also provided. In a group of modalities, the protein kinase activators, dependent on cGMP, are used alone. In another group of embodiments, the protein kinase activators, dependent on non-specific cyclic nucleotides, are used alone. In yet another group of embodiments, activators of the cyclic non-specific nucleotide-dependent protein kinase are used in combination with smooth muscle relaxants. In yet another group of embodiments, the protein kinase activators, dependent on cAMP, are provided in combination with the Ca2 + channel blockers, of type L. In yet another aspect of the present invention, compositions for the treatment of Anorectal disorders, comprising an estrogen or other estrogenic compound, either alone or in combination with another agent. Methods for using these compositions are also provided. In a group of modalities, the estrogenic compounds are used alone. In another group of modalities, the estrogenic compounds are used in combination with a second agent, selected from phosphodiesterase inhibitors, β-adrenergic receptor agonists, cti-adrenergic antagonists, Ca2 + channel blockers, L-type blockers, channel activators. of K + sensitive to ATP, or smooth muscle relaxants, in combination with a pharmaceutically acceptable carrier. The present invention also provides methods of using these compositions. Methods to treat anorectal disorders are also provided. The methods of the invention comprise administering to a subject a suitable formulation of one or more of the above compositions. In related methods, the treatment is carried out by the administration of two or more agents, in sequence, or by the same route of administration or by different administration routes.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 illustrates a typical waveform pattern for latent IASP in a rat under conditions of a control experiment. Figure 2 illustrates the waveform pattern for IASP in a rat following the administration of 20 μl of a 1% solution of nitroglycerin in propylene glycol. Figure 3 illustrates the effect of a cGMP mimetic on the internal pressure of the anal sphincter in a rat. The figure shows the waveform pattern for said IASP for a rat, followed by the administration of 10 μl of a 10% solution of dibutyryl-cGMP in a saline solution. Figure 4 illustrates the effect of a phosphodiesterase inhibitor on internal anal sphincter pressure in a rat. The figure shows a waveform pattern for the IASP for a rat, followed by the administration of 20 μl of a 5% solution of zaprinast in 1-methyl-2-pyrrolidinone.

Figure 5 illustrates the effect of an opening element of the potassium channel on the internal anal sphincter pressure in a rat. The figure shows a waveform pattern for the IASP for a rat, followed by the administration of 10 μl of a 4% solution of minoxidil in 62.5% propylene glycol.

DETAILED DESCRIPTION OF THE INVENTION Abbreviations and Definitions cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; NO, nitric oxide; NTG, nitroglycerin; SOD, superoxide dimutase; PDE, phosphodiesterase; IASP, anal sphincter internal pressure; Rp-cAMPS, Rp-adenosine-3 ', 5'-cyclic monophosphorothioate; Sp-cAMPS, Sp-adenosine.3'.5-cyclic monophosphorothioate; 8-CPT cAMP, sodium salt of 8- (4-chlorophenylthio) -adenosine-3 'monophosphate, 5 • -cyclic; SP-5, 6-DCI-cBiMPS, SP-5, 6-dichloro-l-b-D-ribofuranosylbenzimidazol-3 ', 5'-monophosphorothioate; dibutyryl-cAMP, sodium salt monohydrate of N6, 2'-O-dibutyryladenosine-3'-5-cyclic monophosphate; Sodium salt of Sp-8-pCPT-cGMPS monophosphate, Sp-8- (4-chlorophenylthio) -cuanosine-3'-5-cyclic, - sodium salt of 8-bromo-cGMP monophosphate, 8-bromoguanosine-3 ' , 5 '-cyclic; Sodium monophosphothioate salt of Rp-8-Br-cGMPS, Rp-8-bromoguanosine-3'-5'-cyclic; sodium salt of dibutyryl-cGMP, N2, 2'-O-dibutyrylguanosine-3 ', 5'-cyclic monophosphate; NASH, erythro-9- (2-hydroxy-3 -nonyl) adenine HCl; IBMX, 3-isobutyl-1-methylxanthine; MY-5445, 1- (3-chlorophenylamino) -4-phenylphthalazine; Ro 20-1724, 4- (3-butoxy-4-methoxybenzyl) -2-imidazolidinone. Unless defined otherwise, all technical and scientific terms used herein have the same meanings commonly understood by ordinary experts in the subject matter to which this invention pertains. The following references provide a person skilled in the art with a general definition of many of the terms used in this invention: Singelton et al., DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY (2nd Ed. 1994); THE CAMBODY DICTIONARY OF SCIENCE AND TECHNOLOGY (Walker Ed., 1988); and Hale & Marham, THE HARPER COLLINS DICTIONARY OF BIOLOGY (1991). As used herein, the following terms have the meanings ascribed to them, unless otherwise specified. Although any method and material similar or equivalent to those described herein can be used in the practice or testing of the present invention, preferred methods and materials are described. For the purposes of the present invention, the following terms are defined below. The terms "treatment", "therapy" and the like include, but are not limited to, changes in the status of the recipient. The changes can be subjective or objective and can be related to the characteristics, such as the symptoms or signs of the disease or condition concerned. For example, if the patient notices that the itching decreases, the bleeding is reduced, the discomfort is reduced, the pain decreases, then a successful treatment has occurred. Similarly, if the clinician notes objective changes, such as by the histological analysis of a biopsy sample, then the treatment has also been successful. Alternatively, the clinician may notice a decrease in the size of the lesions or other abnormalities under examination of the patient. This would also represent an improvement to a successful treatment. The prevention of deterioration of receiver status is also included by the term. The therapeutic benefit includes any of a number of subjective or objective factors that indicate a response to the condition being treated, as discussed here. "Drug", "pharmacological agent", "pharmaceutical agent", "active agent" and "agent" are used interchangeably and are intended to have a broader interpretation, as to any active substance therapeutically, which is delivered to a living organism produce a beneficial effect usually, desired. "Pharmaceutically acceptable" or "therapeutically acceptable" refers to a substance that does not interfere with the effectiveness or biological activity of the active ingredients and that are not toxic to the host, which may be humans or animals, to which they are administered. "Therapeutically effective amount" refers to the amount of an active agent sufficient to induce a desired biological result. That result can be the relief 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 the applied formulation. The appropriate amounts, in any given case, will be readily apparent to those skilled in the art or capable of determination by routine experimentation. The term "anorectal area" is defined herein to include both the anus and the rectal region of a mammal. More particularly, the term includes the internal anal canal, the external anus, and the inferior rectus. "Hypertonicity" refers to a normal state of normal muscle tension or incomplete relaxation.

The term "cyclic nucleotide" refers to cyclic adenosine monophosphate and cyclic guanosine monophosphate d. The term "modulation" refers to any systematic variation or graduated change in a characteristic (eg, frequency, concentration, amplitude, effectiveness, etc.) of a sustained oscillation, sufficient to affect a biological function. The term "change" includes an increase or decrease in the characteristic. The term "subject", as used herein, includes an animal, such as a mammal, that includes a human. The term "anorectal disorder" includes any disorder associated with anal rectal disease, including anal fissures, acute or chronic, a thrombosis hemorrhoid, internally or externally, a hemorrhoidal disease, a disorder associated with the endoscopic hemorrhoidal pain ligament, caused by such a ligament, levator spasm, constipation and other anorectal disorders, caused by the hypertonicity or spasm of the anal sphincter muscle. The term "anal fissure" is also referred to as "anal spasms" of the anal sphincter and also as "rectal tenasmo or pujo". Additionally, the term includes pain that may be associated with any of the above conditions or conditions.

The term "potassium channel opening element" and "potassium channel activator" generally refers to a class of drugs that causes an increased flow of potassium ions from the interior of a cell, electrically excitable, to the outside the cell, through a membrane of this cell, which has at least one potassium channel. The opening activity of the potassium channel can be observed by measuring the hyperpolarization of the cell membrane potential (ie, a more negative membrane potential) caused by an increase in the flow of potassium ions from inside a cell to the cell. outside of it by means of a potassium channel in the cell membrane. The term "pharmaceutical composition" means a composition suitable for pharmaceutical use in a subject, which includes an animal or human. A pharmaceutical composition generally comprises an effective amount of an active agent and a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" encompasses any of the standard pharmaceutical carriers, regulators and excipients. which include a saline solution regulated with phosphate, water, and emulsions (such as oil / water or water / oil emulsions) and various types of wetting and / or auxiliary agents. Suitable pharmaceutical carriers and their formulations are described in REMINGTON'S PHARAMACEUTICAL SCIENCES (Mac Publishing Co., Easton, 10 Ed. 1995). Preferred pharmaceutical carriers depend on the mode of administration attempted of the active agent. Typical modes of administration are described below. The term "effective amount" means a dose sufficient to produce a desired result. This desired result may comprise an objective subjective improvement in the recipient of the dose. 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, in which the treatment is administered in order to decrease the risk of developing a pathology. A "therapeutic treatment" is a treatment administered to a subject which exhibits signs of pathology, where the treatment is administered in order to decrease eliminate those pathological signs. The term "appropriate anal area" means any area or tissue of the anus or sphincter, which is affected by or subjected to an anal disorder or disease, including, for example, the external and internal anus, the external anal sphincter or internal, the anal sphincter muscle, or the external or internal anal canal.

As used herein, the term "NO donor" refers to any compound, organic or inorganic, which can deliver nitric oxide in a physiological medium. Also included are those compounds that can be metabolized in vivo to a compound that delivers the nitric oxide (for example, a prodrug form of a NO donor, or a binary NO generator).

General Data A promising new approach to treating anal disorders is the topical application of a nitric oxide (NO) donor to an appropriate anal area. The nitric oxide has been shown to cause a reduction, dependent on the concentration in the latent tension of the smooth muscle strips of the internal sphincter in vi tro (Rattan et al., Am. J. Physiol .262: G107-112 (1992) ), and NO donors (eg, nitroglycerin, isosorbide dinitrate, isosorbide mononitrate and L-arginine) have been shown to reduce anal pressure in humans. Schouten, W. R. et al., "Pathophysiological Aspects and Clinical Results of the Intra-Anal Application of Isosorbide Dinitrate in Patients with Chronic Anal Fissures", Gut 39: 465-9 (1966); Farid, M, Br. J. Surg.84: 1 (1997); and Hechtman, H.B. et al.,. Arch. Surg. 131: 115-118 (1996). NO has also been shown to intervene in the relaxation of adaptation of other sphincters in the gastrointestinal tract, which include the sphincter of the lower esophagus (Conklin et al., Gastroenterology 104 1439-1444 (1993); Tottrup et al., Br. J. Pharmacol 104: 113-115 (1991), pyloric sphincter, (Bayguinov et al., Am. J. Physiol. 264-.G975-983 (1993), Oddi sphincter (Mourelle et al., Gastroenterology 105: 1299-1305 (1993)), and the ileocolic sphincter (Ward et al., Br. J. Pharmacol. N105: 776-782 (1992)) It is thought that NO or NO-like substances serve as important control mechanisms for the phenomenon General of Gastrointestinal Adaptation Relaxation Despite initial hope of NO donors, tachyphylaxis has been observed for members of this class of agents Surprisingly, the present invention provides compositions that are useful in overcoming side effects and problems associated with current therapies.

Description of Modalities Nitric oxide (NO) donors in combination with a Second Agent In one aspect, the present invention provides compositions for the treatment of anal disorders, comprising a nitric oxide donor in combination with a second agent, which modulates the levels of cAMP or e cGMP. In a group of modalities, the second agent is or inhibitor of type V phosphodiesterase (PDE V). In another group of modalities, the second agent is a type IV phosphodiesterase (PDE IV) inhibitor. In another group of modalities, the second agent is an inhibitor of type II phosphodiesterase (PDE II). In another group d modalities, the second agent is an inhibitor of n-specific PDE. In yet another group of modalities, the second agent is a superoxide anion debugger (02 ~). And yet another group of modalities, the second agent is a β-adrenergic agonist. In another group of modalities, the second agent is an activator of the protein kinase, dependent on cAMP. In another group of modalities, the second agent is an oci-adrenergic antagonist. In another group of modalities, the second agent is an estrogen, estrogen analog, or an estrogenic compound. In another group of modalities, the second agent is a Ca2 + channel blocker of type L. In yet another group of modalities, the second agent is a K + channel activator, sensitive to ATP. The present invention further provides methods of using the compositions provided above. In a related aspect, the present invention provides compositions comprising a NO donor and a smooth muscle relaxant. In each of the above embodiments, the nitric oxide donor can be any of a variety of NO donors, including, for example, organic NO donors, inorganic NO donors and forms of prodrugs of NO donors. Preferably, the NO donor includes at least one organic nitrate (which includes the nitric acid esters) and can be cyclic or acyclic compounds. For example, suitable donors of the NO 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-1,2-dinitrate, glyceryl-1,3-dinitrate, butan-1,2,4-triol-trinitrate and the like. More preferably, the NO donor is the NTG. Nitroglycerin and other organic nitrates, including ISDN, ETN and PETN, have had regulatory approval for use in treatments in other fields of medicine in human subjects. Additional NO donors include sodium nitroprusside, N, 0-diacetyl-N-hydroxy-4-chlorobenzenesulfonamide, Is-hydroxy-L-arginine '(NOHA), hydroxyguanidine sulfate, molsidomine, 3-morpholino sidononimine (SIN-1). ), (+) -S-nitroso-N-acetylpenicilamin (SNAP), S-nitrosoglutadione (GNSO), (±) - (E) -ethyl -2- [(E) hydroxyimino] -5-nitro-3-hexanamide (FK409), (+) -N- [(E ) -4 ethyl-3- [(Z) -hydroximino] -5-nitro-3-hexen-l-yl] -3-pyridinecarboxamide (FE244420) and 4-hydroxymethyl-3-furoxan-carboxamide. In general, the organic nitric oxide donor, which includes organic nitrate, is present in any minor amount of which is effective in the practice of treating anal disease, when used alone. In the typical practice of the invention, the donor of the organic nitric oxide may be present in a concentration of about 0.01 to 10 weight percent. All percentages by weight here are based on the total weight of the composition. For NTG, preferred concentrations are in the approximate range of 0.01 to 5 percent by weight. In a group of embodiments, the composition contains an agent which is a type V phosphodiesterase inhibitor (PDE V). Phosphodiesterase (PDE) inhibitors are agents that can block the disruption of cAMP and cGMP in tissue. PDE inhibitors include both non-specific PDE inhibitors and specific PDE inhibitors (which inhibit a single type of phosphodiesterase with little, if any, effect on any other type of phosphodiesterase). Inhibitors of type V phosphodiesterase include azprinast, MBCQ, MY-5445, dipyridamole and sildenifil. In another group of embodiments, the composition contains an agent which is an inhibitor of phosphodiesterase type II (PDE II). Suitable inhibitors of type II phosphodiesterase include NASH. In yet another group of embodiments, the composition contains an agent which is an inhibitor of type IV phosphodiesterase (PDE IV). Suitable inhibitors of type IV phosphodiesterase include arifle (SB207499), RP73401, CDP840, rolipram and LAS31025. In yet another group of modalities, the composition contains an agent which is a non-specific phosphodiesterase inhibitor (non-specific PDE). Inhibitors of the appropriate non-specific phosphodiesterase, includes IBMX, theophylline, aminophylline, pentoxifylline, papaverine and caffeine. In yet another group of modalities, the composition contains an agent which is a superoxide anion scavenger (02 ~). This superoxide can react with NO and drastically reduce its biological effects. Therefore, the agents that purify the superoxide anion (for example the exogenous Mn- or Cu / Zn superoxide dimutase (SOD) or imitators of the small molecule SOD, for example the Mn (III) tetra (4-) benzoic acid) chloride d porphyrin (MnTBAP) and M40403, see Salvemini, et al., Scienc 286 (5428): 304-306 (1999)), can intensify the effects of NO. SODs are relatively stable enzymes and can be used in topical formulations with NO donors, such as, for example, NTG, to boost the local potency of NOG generated from NTG. The nitric oxide formed by NTG acts only locally due to its short half-life. However, the NTG itself is sufficiently stable to exert systemic effects immediately after mucosal uptake. By increasing the local efficacy of NTG with SOD, or an SOD imitator, less NTG is required to produce the same degree of relaxation of the internal anal sphincter minus NTG will be absorbed, leading to a reduction in systemic side effects. In yet another group of modalities, the composition contains an agent which is a β-adrenergic agonist, preferably a β2- or β3-adrenergic receptor agonist. A variety of β-adrenergic agonists have been described in the literature and are useful in the present invention. Suitable ß-adrenergic agonists are described in, for example, Bristol, et al., ANNUAL REPORTS IN MEDICINAL CHEMISTRY, Vol. 33, Chap. 19, pp 193-202, Academic Press (q998). Preferred β-adrenergic agonists include salbutamol, terbutalin, procaterol clenbuterol, isoproterenol, zinterol, BRL 37344, CL316243, CGP-12177A, G 332, L-757793, L-760087, L-764646 and L-766892. In another group of modalities, the agent is the activator of the protein kinase dependent on cAMP. A variety of protein kinase activators, dependent on cyclic nucleotides, are useful in the present invention, including, for example, cAMP mimics and dual cGMP / cAMP-dependent protein kinase activators. CAMP mimics are well known to those skilled in the art and include 8-bromo-cAMP, dibutyryl-cAMP, Rp-cAMPS and Sp-cAMPS. Double activators include the Sp-8-pCPT-cGMPS, Sp-8-bromo-cGMPS and 8-CPT-cAMP. In yet another group of modalities, the composition contains an agent which is an estrogen or an analog or an estrogen mimic. As used herein, the term "estrogen" means the inclusion of all forms of estrogen and estrogen-type compounds, such as those compounds that have an estrogen-like activity. (for example, those that bind to the estrogen receptor in a competitive binding assay). Estrogens can be either steroidal or non-steroidal (see, for example, Bristol, et al ANNUAL REPORTS IN MEDICINAL CHEMISTRY, Vol.31, Ch.19, pp181-190, Academic Press (1996) and references cited therein) . Estrogen-type compounds include, but are not limited to, 17-beta estrodiol, estrous, mestranol, estradiol valerate, estrodiol dipionate, ethinyl estrodiol, quinestrol, estrone sulfate, phytoestrogens, such as falvones, isoflavones ( example genistein), resveratrol, derivatives of coumestan, other synthetic estrogenic compounds, which include pesticides (eg, ep, p'-DDT), plasticizers (eg bisphenol A) and a variety of other industrial chemicals (eg example, polychlorinated biphenyls). In yet another group of modalities, the composition contains an agent which is an ax-adrenergic antagonist. The sympathetic neurotransmitter norepinephrine contracts the smooth muscles of the sphincter by means of α-α-adrenergic receptors. Pharmacological interference with the release of norepinephrine or binding to α-adrenergic receptors by the administration of sympatholytic agents to the appropriate anal area of a subject may also lead to relaxation of the anal sphincter and improvement of the signs and symptoms of anorectal disorders. These sympatholytic agents include ax-adrenergic receptor antagonists (eg, prazosin, doxazosin, phentolamine, tolazoline and the like, as described in THE PHARMACOLOGICAL BASIS OF THERAPEUTICS by Goodman &Gilman, ninth edition Ed. JG Hardman, et al. ., McGraw-Hill 1996), the a2-adrenergic agonists, which block the release of norepinephrine (for example clonidine), the agents that decrease the norepinephrine end of nerves (for example, guanethidine, bretylium, reserpine), inhibitors of the synthesis of norepinephrine (for example a-methyl-tyrosine) and agents that destroy the sympathetic nerve terminals (for example 6-hydroxydopamine). Therefore, in a related embodiment, the composition contains an alternative sympatholytic agent, such as an a2-adrenergic receptor agonist, an agent that decreases nerve terminal norepinephrine, an inhibitor of norepinephrine synthesis or another agent that destroys sympathetic nerve terminals. In yet another set of modalities, the agent is an ATP-sensitive K + channel activator. ATP together with NO, is thought to serve as an inhibitory neurotransmitter released from non-cholinergic non-adrenergic nerves, which involve adapted relaxation of gastrointestinal smooth muscle (Burnstock, Pharmacol Rev. 24: 509-81 (1972)) . ATP appears to act primarily by opening the ATP-sensitive potassium channels (KATP), which hyperpolarize the cell membrane, reducing intracellular calcium concentrations, leading to smooth muscle relaxation. The synthetic compounds that activate the K + channels sensitive to ATP are smooth muscle relaxants, for example, minoxidil, minoxidil sulfate, pinocidil, diazoxide, levcromakalim, cromakalim, etc. (see White, et al., Eur. J. Pharmacol. 357 (1) 41-5 (1998)). The ATP-sensitive potassium channels are expressed Gl smooth muscles (Koh, et al., Biophys, J. 75: 1793-80 (1998)). Therefore, the elements that open the specific potassium channels will be useful to relax the smooth muscle of the internal anal sphincter and improve the signs and symptoms of anorectal disorders. It should be noted that other K + channels may also have an influence on smooth muscle tone, which includes K + channels, activated calcium, low conductance, sensitive to apamin, and activated high calcium K channels. conductance, sensitive to caribdotoxin. In still other modalities, the compositions will include NO donors and smooth muscle relaxants. Preferred smooth muscle relaxants include, for example, hydralazine, papaaverine, tiropramide, cycloandelate, isoxsuprine or nilidrine.

Phosphodiesterase Inhibitory Compositions In another aspect, the present invention provides compositions for the treatment of anorectal disorders, comprising an inhibitor of phosphodiesterase, preferably a PDE II inhibitor, a PDE IV inhibitor or a PDE V inhibitor. , either alone or in combination with another agent, selected from ß-adrenergic receptor agonists, cti-adrenergic antagonists, estrogens, L-type Ca2 + channel blockers, K + channel activators, ATP-sensitive, or relaxant agents of the smooth muscles, and combination with a pharmaceutically acceptable carrier. The present invention also provides methods of using these compositions.

Inhibitors of phosphodiesterase (inhibitors) PDE) are agents that can block the disruption of cAMP and cGMP in the tissue. PDE inhibitors include non-specific PDE inhibitors and specific PDE inhibitors. A nonspecific 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 in any other type of phosphodiesterase. Specific inhibitors of five families of cyclic nucleotide PDE isozymes have been characterized: 8-methoxymethyl-IBMX (isobutyl methyxanthine) or vinpocetine (Ca2 +, type of PDE dependent on calodulin); EHNA (erythro-9- (2-hydroxy-3-ninyl) adenine HCl) (PDE type II stimulated by cGMP); milrinone (type III PDE inhibited by cGMP); rolipram (and type IV of cAMP-specific PDE); and zaprines and DMPPO (1,3-dimethyl-6- (2-propoxy-5-methanesulfonyl amidophenyl) -pyrazolo [3,4-d] pyrimidin-4- (5H) -one) (type V d specific PDE of cGMP). Current knowledge suggests that there are at least nine classes of pDE isozymes with the recently discovered type 9A (see Fisher e al., J. Biol., Chem.213 (25); 15559-15564 (1998)) . Agents that are non-specific PD inhibitors include, for example, IBMX, theophylline, aminophylline, caffeine, etc. (see Vemulapalli, et al., J. Cardiovasc Pharmacol 28 (6): 862-9 (1996)). Preferably, the compositions for the treatment of anorectal disorders contain one or more compounds selected from the classes of inhibitors PD II, PDE IV and PDE V in a formulation suitable for local treatment. Members of each of these classes can advantageously be combined with a second agent, selected from the group of β-adrenergic receptor agonists, preferably β2-adrenoceptor agonists, β-adrenergic agonists, cti-adrenergic antagonists, Ca2 + channel blockers, type L, estrogen, activators of the K + channel sensitive to ATP or smooth muscle relaxants. Preferred members of each class of additional agents are those that have been described above for the use of NO donors.

[Beta] -Adrenergic receptor agonist compositions In another aspect, the present invention provides pharmaceutical compositions for the treatment of anorectal disorders, comprising a β-adrenergic receptor agonist, preferably a β2-β3-adrenergic receptor agonist, either alone or in combination with another agent, selected from PDE inhibitors that hydrolyze cAMP (for example the PDE IV inhibitor), inhibitors of the Non-specific PDEs, α-adrenergic antagonists, estrogen, L-type Ca 2+ channel blockers, ATP-sensitive K + channel activators, or smooth muscle relaxants, and a pharmaceutically acceptable carrier. The present invention also provides methods of using those compositions. In this aspect of the invention, the β-adrenergic receptor agonist can be essentially any β-adrenergic receptor agonist provided above for use in combination with NO donors. Preferably, the β-adrenergic agonist is a β2- or β3-adrenergic receptor agonist. Particularly preferred β-adrenergic agonists are those described in Bristol et al., ANNUAL REPORTS IN MEDICINAL CHEMISTRY, Vol. 33, Chap. 19, pp. 193-202, Academic Press (1998) or are selected from salbutamol, terbutaline, streptol, clenbuterol, isoproterenol, zinterol, BRL 37344, CL316243, CGP12177A, GS 332, L-757793, L-764646 and L-766892. In a group of embodiments, the composition contains a suitable β-adrenergic receptor agonist and a pharmaceutically acceptable carrier, preferably one formulated for local delivery to the site of the disease or anorectal disorder. In another group of embodiments, the composition contains another agent selected from PDE inhibitors, which hydrolyze cAMP (e.g., a PDE inhibitor).

IV), nonspecific PDE inhibitors, oci-adrenergic antagonists, estrogens, L-type Ca2 + channel blockers, ATP-sensitive K + channel activators or smooth muscle relaxants. In a preferred group of embodiments, the agent is a PDE inhibitor that hydrolyzes cAMP, more preferably an inhibitor of type IV phosphodiesterase. Preferred inhibitors of type IV phosphodiesterase (also referred to as PDE IV and PDE4) are described in, for example, Bristol, et al., ANNUAL REPORTS IN MEDICINAL CHEMISTRY, Vol. 33, Chap. 10, pp. 91.109, Academic Press (1998). More preferably, the PDE IV inhibitor is rolipram, Ro 20-1724 or Etazolate. In another group of preferred embodiments, the agent is a non-specific PDE inhibitor, such as, for example, IBMX, aminophylline, theophylline, pentoxifylline, lyophilin and papaverine. In yet another group of preferred embodiments, the agent is an α-adrenergic antagonist. Suitable antagonists of the α-adrenergic receptors (e.g. prazosin, doxazosin, phentolamine, tolazoline, and the like) are described in THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, DE Goodman & Gilman, ninth edition. Ed. JG. Hardman, et al., McGraw-Hill (1996). Preferred agents for use in these compositions are selected from prozosin, doxazosin, phentolamine tolazoline and their derivatives. In still other preferred embodiments, the β-adrenergic receptor agonist is combined with an L-type Ca 2+ channel blocker, such as, for example, nifedipine, nimodipne, felopidine, nicardipine, isradipine, amlodipine, diltiazem and verapamil. In yet other preferred embodiments, the β-adrenergic receptor agonist is combined with the activator of the K + channel sensitive to ATP. Preferred agents within this group are the same as those that have been previously provided for use with NO donors. Additional compositions are those in which the β-adrenergic receptor agonist is combined with an estrogen or an 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.

Compositions that activate the potassium channel In yet another aspect, the present invention provides compositions for the treatment of anorectal disorders, comprising an activator of the K + channel sensitive to ATP, either alone or in combination with other agents, selected from the activators of cAMP-dependent protein kinase, estrogens, ax-adrenergic antagonists, L-type Ca2 + channel blockers, or smooth muscle relaxants, and a pharmaceutically acceptable carrier. The present invention also provides methods of using those compositions.

In this aspect of the invention, the combinations selected are obtained from the components described above in detail for the compositions of the NO donation. A further description of ATP-sensitive potassium ion anal activators can be found in, for example, Bristol, et al. ANNUAL REPORTS I MEDICINAL CHEMISTRY, Vol. 29, Chap. 8, pp. 73-82, Academic Press (1991). In preferred embodiments, the activator of the potassium ion channel is diazoxide, minoxidil, PCO 400, pinocidil, levcromokalin or cromokalim. In some embodiments, the composition comprises an additional agent which is an activator of the protein kinase., dependent on cAMP, an estrogen or a compound similar to estrogen, an ai-adrenergic antagonist, a L-type Ca2 + channel blocker, or a smooth muscle relaxant. Preferably, the cAMP-dependent protein kinase activator is a cAMP mimic or a double activator of cGMA / cAMP-dependent protein kinase. More preferably, the cAMP mimic is 8-bromo-cAMP, dibutyryl-cAMP, Rp-cAMPS or Sp-cAMPS, and the double activator is selected from Sp-8-pCPT-cGMP, Sp-8-bromo-cGMPS and 8-CPT-cAMP.

In one group of modalities, an ax-adrenergic antagonist is combined with an activator of the potassium ion channel sensitive to ATP. Preferably, the oti-adrenergic antagonist is prazosin phentolamine or tolazoline. In another group of modalities, a blocker of the Ca2 + channel, of type L, is combined with an activator of the potassium ion channel, sensitive to ATP. Preferably, the L-type Ca2 + channel blocker is nifedipine, nimodipine, felopidine, nicardipine, isradipine, amlodipine, diltiazem or verapamil. In yet another group of modalities, a smooth muscle relaxant is combined with the activator of the potassium ion channel, sensitive to ATP. Preferably, the smooth muscle relaxant is hydralazine, papaverine tiropramide, cycllandelate, isoxsuprine or nilidrine.

Antagonist Compositions GCi-adrenergic In yet another aspect, the present invention provides compositions for the treatment of anorectal disorders, comprising an ai-adrenergic antagonist, either alone or in combination with another agent, selected from PDE inhibitors, which hydrolyze the cAMP (preferably a PDE IV inhibitor), oestrogens or smooth muscle relaxants, and a pharmaceutically acceptable carrier. The present invention also provides methods of using those compositions. The α-adrenergic antagonists, which are useful in this aspect of the invention, have been described above and can be found in, for example, THE PHARMACOLOGICAL BASIS OF THERAPEUTICS by Goodman & Gilman, ninth edition. Ed. JG. Hardman et al., McGraw-Hill (1996). Preferred ax-adrenergic antagonists are prazosin, phentolamine and tolazoline. For those modalities in which the cti-adrenergic antagonist is combined with a PDE inhibitor that hydrolyzes cAMP (preferably a PDE IV inhibitor), an estrogen or estrogen-like compound, or a smooth muscle relaxant, the members Preferred of each class are those that have been described above for use with NO donors.

Compositions of Cyclic Nucleotide-dependent Protein Kinase Activator In another aspect, the present invention provides pharmaceutical compositions for the treatment of anorectal disorders comprising cyclic nucleotide-dependent protein kinase activators, either alone or in combination with another. agent. Methods for the use of these compositions are also provided. In a group of modalities, the protein kinase activators, dependent on cGMP, are used alone. In another group of embodiments, the protein kinase activators, dependent on non-specific cyclic nucleotides, are used alone. In yet another group of modalities, activators of the nonspecific cyclic nucleotide dependent protein kinase are used in combination with smooth muscle relaxants. In yet another group of modalities, cAMP-dependent protein kinase activators are provided in combination with the L-type Ca2 + channel blockers.

In each case, the preferred members of the aforementioned classes of compounds are those that were described above for use alone or in other combinations.

Estrogen and imitative estrogen compositions In another aspect, the present invention provides pharmaceutical compositions for the treatment of anorectal disorders, comprising estrogen or an estrogen mimic, either alone or in combination with another agent of any of the classes of agents described above. . Estrogen-type compounds include, but are not limited to, 17-beta-estradiol, estrone, mestranol, estradiol valerate, estrodiol dipionate, ethinyl estrodyl, quinestrol, estrone sulfate, phytoestrogens, such as falvones, isoflavones. (for example genistein), resveratrol, coumestan derivatives, other synthetic estrogenic compounds, which include pesticides (for example p, p'-DDT), plasticizers (for example bisphenol A), and a variety of other chemicals industrial agents (for example polychlorinated biphenyls) (Goodman / Gilman, in 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 compositions of simple agents or combinations above The methods for the use of these compositions are also provided.

Formulations for the Treatment of Anorectal Disorders Many of the individual components of the above compositions have been described for use in a variety of disease states. However, certain classes and combinations of classes have now been found useful for the treatment of anorectal diseases and can be provided in formulations best suited for delivery to an appropriate anal area. Preferred formulations are those in which the components are combined in a topical formulation for local application to the external and internal anus, the external or internal anal sphincter, the anal sphincter muscle, the external or internal anal canal and the lower rectum above the anal channel. Therefore, each of the compositions provided above will typically be presented in an appropriate pharmaceutical formulation, comprising an effective amount of the aforementioned agents (eg, NO donors, β2- or β3-adrenergic receptor agonists, beta-blockers), PDE, which hydrolyze cAMP, nonspecific PDE inhibitors, ai-adrenergic antagonists, L-type Ca2 + anal blockers, ATP-sensitive K + channel activators, and the like). One skilled in the art will appreciate that suitable formulations are dependent on the delivery form employed, and all such forms are considered by the present invention. Additionally, in some embodiments, combinations of agents are employed in a simple formulation, while, in other embodiments, the agents are formulated separately, but administered in combination, or in sequence. In the following discussion, the compositions of simple agents will also be understood to include compositions of two or more agents. Furthermore, the different formulations can be used for those modalities in which the agents are administered separately or in sequence by different administration routes.

Topical compositions In view of the foregoing, the present invention provides topical compositions useful for the treatment of anorectal disorders (including those related to hypertonicity and / or spasm of the internal anal sphincter muscle, eg, hemorrhoidal pain) and for the spasm treatment of a mammal, including humans, comprising an effective amount of an agent that prevents contraction of the anal sphincter muscle and a pharmaceutically acceptable carrier. In one embodiment, the agent is a potassium channel opener, sensitive to ATP. In another embodiment, the agent is an inhibitor of phosphodiesterase, a cyclic nucleotide mimic, a β-adrenergic agonist, an estrogen or estrogen-type compound, and a ccx-adrenergic antagonist. In related embodiments, the present invention provides topical pharmaceutical compositions in unit dosage form, comprising per unit dose an amount of the agent or combination provided above, which is effective in treating an anal disorder in a subject in need of such treatment, Typically, the agents are in combination with a pharmaceutically acceptable carrier. Such compositions are useful in treating or reducing the pain associated with anal disorders, such as hemorrhoidal pain, and to treat spasms and / or hypertonicity of the sphincters, which include 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 spasm and / or sphincter hypertonicity of the anorectal region, which includes anal fissure, post-operative rectal pain, hypertrophic pyloric stenosis and pancreatitis, as well as resulting conditions. of general spasm of muscles of the Gl tract including Zenkers diverticulum, achalasia, spasm of the esophagus (nutcracker esophagus), irritable bowel disease and Hirshprungs disease (obstruction of the bowel). In addition, topical compositions are useful for relaxing the anal sphincter and reducing pain before, during or after examinations of the anus, rectum and lower gastrointestinal system, insertion of instruments and procedures, such as surgery.

Dosage Forms Dosage forms for topical administration of the anal sphincter relaxants of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, suppositories and liposomal preparations. The dosage forms can be formulated with mucoadhesive polymers for the sustained release of the active ingredients in the anal mucosa. The active compound can be mixed, under sterile conditions, with a pharmaceutically acceptable carrier and with any condom, regulator, or impeller, as may be required. Topical preparations can be prepared by combining the anal sphincter relaxant with conventional pharmaceutical diluents and carriers, commonly used in dry topical, liquid, cream and aerosol formulations. The ointments and creams can, for example, be formulated with an aqueous or oily base, with the addition of suitable thickening and / or gelling agents. Such bases may include water and / or an oil, such as liquid paraffin or a vegetable oil, such as peanut oil or castor oil. Thickening agents that can be used, according to the nature of the base, include mild paraffin, aluminum stearate, cetostearyl alcohol, propylene glycol, polyethylene glycols, wool fat, hydrogenated lanolin, beeswax and the like. The lotions can 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 similar. The powders can be formed with the aid of any suitable powder base, for example, talc, lactose, starch and the like. The drops can be formulated with an aqueous base or a non-aqueous base, which also comprises one or more dispersing agents, suspending agents, solubilizing agents and the like.

Ointments, pastes, creams and gels may also contain excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth gum, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, taco and rust. of zinc or its mixtures. The powders and sprays may also contain excipients, such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may additionally contain customary impellers, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

Representative compositions include topical compositions, which comprise one or more of the following first pharmacological agents: a NO donor, a phosphodiesterase inhibitor, a cyclic nucleotide mimic, a β-adrenergic agonist, a calcium channel blocker of the L type , an α-adrenergic antagonist, an activator of the potassium channel, sensitive to ATP, estrogen or an estrogen-like compound, or botulinum toxin in combination with a pharmaceutically acceptable carrier and at least one of the following second pharmacological agents: an anesthetic local (for example, lidocaine, prilocaine, etc.), a local anti-inflammatory agent (eg naproxen, pramoxicam, etc.), corticosteroids (eg cortisone, hydrocortisone, etc.) an anti-itch agent ( for example, loperamide difilenoxalate, etc.), an agent that interferes with the activation of peripheral sensory neurons, which include metal ions divalent and trivalent (for example manganese, calcium, strontium, nickel, lanthanum, cerium, zinc, etc.), analgesic agents, yeast-based products (for example freeze-dried yeast, yeast extract, etc.), promoters of the growth and / or agents that promote wound healing, known to promote re-epithelialization (eg PDGF of platelet-derived growth factor), interleukin-11 (IL-11) etc.), anti-microbial agents (eg neosporin, polymyxin B sulfate, zinc d bacitracin, etc.), mucoadhesive agents (for example cellulose derivatives, etc.) , cytoprotective agents (for example colloidal bismuth, misoprostol, etc., with the exception of sucralfate), as defined in GOODMAN GILMAN 'S THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, supra, an agent that promotes sclerosis of local tissues (eg alum, etc.) or menthol. This at least one first pharmacological agent is typically present in the composition in unit dosage form for an effective treatment for first medical conditions, such as an anal disease or associated pain. This at least one second pharmacological agent is typically present in the composition in a unit dosage form effective for the treatment of a second medical condition or one or more symptoms of conditions or effects associated with or resulting from the first medical condition. In one aspect, the invention provides compositions for treating anorectal disorders, comprising an active agent and a pharmaceutically acceptable carrier. The active agent comprises an agent that stimulates or causes an increase of either cGMP or cAMP, through the activation of guanylyl or adenylyl cyclase, respectively, a mimetic of the cyclic nucleotide, a PDE inhibitor, an antagonist of the a-adrenergic receptor, or a β-adrenergic receptor agonist, or the potassium channel opener. In one aspect, the active agent is present in the compositions of the invention, in an amount of about 0.001 to 15% by weight of the composition. In another aspect, the active agent is present in an amount of about 0.01 to 7.5%, by weight or about 0.05 to 2% by weight of the composition. For example, in a group of embodiments, the invention provides compositions for the treatment of anorectal disorders, comprising a pharmaceutically acceptable carrier and an amount of about 0.001 to 15% sildenafil by weight. In another aspect, compositions are provided comprising a pharmacologically acceptable carrier and an amount of about 0.01 to 7.5% or about 0.05 to 2% sildenafil by weight. Topical pharmaceutical compositions may also include one or more preservatives or bacteriostats, for example methyl hydroxybenzoate, propyl hydroxybenzoate, chlorocresol, benzalkonium chlorides, and the like. Topical pharmaceutical compositions may also contain other active ingredients such as antimicrobial agents, particularly antibiotics, anesthetics, antipruritic analgesics. An example of a topical formulation includes 75% (weight (weight) of USP white petrolatum, 4% (weight / weight paraffin wax USP / NF, lanolin 14% (weight / weight), sorbitan sesquiolate NF, 4% propylene glycol USP 1 % of an anal sphincter relaxant agent The dose of sphincter relaxant-specific agent depends on many factors, which are known to those skilled in the art, eg, particular agent, the condition being treated, age, eg and the clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner administering therapy An effective amount of the compound is that which provides or subjective relief of the symptoms or objectively identifiable improvement, as noted by clinician or other observer The dosage varies with the compound used, the route of administration and the potency of the particular compound.The delivery of the transmucosal drug (ie sublingual, rectal, colonic, pulmonary, buccal and vaginal) provides an efficient input of the It activates the systemic circulation and reduces the immediate metabolism by the liver and flora of the intestinal wall (see Chien Y. W., NOVEL DRUG DELIVERY SYSTEMS, Chapter 4, "Delivery of Drug Mucus". Marcel Dekker, Inc. (1992). Dosage forms of transmucosal drugs (eg, tablets, suppositories, ointments, gels, pessary, membrane and powder) are typically kept in contact with the mucosal membrane and disintegrate and / or dissolve rapidly to allow immediate, local and systemic These formulations are used in conjunction with the anti-inflammatory agents of the present invention, to reduce or eliminate inflammation of the transmucosal membranes.

Sustained or controlled delivery formulations In still other embodiments, the invention provides sustained-release and sustained-release topical pharmaceutical compositions, comprising one or more anal sphincter relaxants. including donors of nitric oxide (such as nitroglycerin, isosorbide dinitrate and L-arginine) or the pharmacological agents described above and a pharmaceutically acceptable carrier, to treat anorectal disorders. Such compositions are useful in the treatment of such disorders and in controlling and reducing the pain associated with these disorders. Said compositions may comprise a unit dose of one or more particular active agents (for example a nitric oxide donor) which is effective in treating anal disorders and in controlling and relieving the pain associated therewith. Preferably, the compositions are administered in unit dosage forms to a subject in need of such treatment. In other embodiments, the compositions contain a NO donor in an amount which is less than an effective amount when used alone, but which is effective when used in combination with a second agent, which modulates cAMP or cGMP in a subject. Topical sustained release and prolonged compositions are typically variants that include: 1) an absorbent in a hydrophilic base; 2) an absorbent in a hydrophobic base; and 3) coated globules containing an absorbent matrix dispersed in a suitable vehicle. Also provided are methods for the treatment of anal or Gl tract disorders, comprising topically administering an effective amount of such compositions (eg, in unit dosage form) to the appropriate anal area of the subject in need of such treatment. Such hydrophilic compositions and preparations of the invention comprise a nitric oxide donor (or other suitable agent or combination of agents), and a polymer, such as cellulose (methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, etc.). .), polyethylene glycol of higher molecular weight, emulsion of methacrylic acid-acrylic, hydrogel, carbopol, ethyl copolymer and vinyl acetate, or polyester, etc., to bind the nitric oxide donor to the polymer. The matrix of the nitric oxide donor polymer or the agent-polymer matrix is then dispersed in a hydrophilic carrier to form a semi-solid. After the administration of such a hydrophilic composition in the appropriate anal area, such as the anal canal or anal sphincter, the water in the semi-solid preparation is adsorbed and the polymer matrix with the active ingredient - the nitric oxide donor or another agent - remains as a coating on the anal region or area to which it has been applied. The nitric oxide donor is then slowly released from this coating. The hydrophobic compositions and preparations of the inventions employ similar polymers, as used in the hydrophilic preparations, but the matrix of the polymer / nitric oxide donor is dispersed in a carrier, such as a plastibase, in the hydrophobic compositions and preparations. The plastibase is a mineral oil base that only partially dissolves the nitric oxide donor. The semi-solid composition forms a thin coating in the anal region to which the composition has been applied (such as the anal canal or anal sphincter area) and slowly releases the active substance.

The prolonged action is controlled mainly by the solubility of the active ingredient (nitric oxide donor) in the vehicle. The present invention also provides coated globules which are produced by first absorbing the nitric oxide donor or other agent or combination of agents, in a cellulosic material in admixture with the polyethylene glycol, filler, binder and other excipients. The resulting matrix is then extruded and spheronized (for example the process of obtaining it into spheres) to create small globules. These globules are then coated with an appropriate thickness, with one or more suitable materials, such as the methacrylic-acrylic polymer, polyurethane, ethyl copolymer and vinyl acetate, silastic, etc. The coating on the globules acts as a membrane that controls the regimen, which regulates the release of the agent from the globules of the nucleus.

Oral Formulations In yet another embodiment, the invention provides pharmaceutical compositions suitable for oral administration, which are provided in unit dosage forms comprising per unit dose an inhibitor of phosphodiesterase, cyclic nucleotide analogs, or a β-adrenergic agonist, and a pharmaceutically acceptable carrier. Such compositions are useful in treating anorectal disorders, which include those conditions conditions provided above. For delivery to buccal membranes, an oral formulation, such as pills, tablets or capsules, is typically used. The method of manufacturing these formulations is known in the art, including, but not limited to, the addition of a pharmacological agent to a previously manufactured tablet; cold compression of an inert filler, a binder, and a pharmacological agent or a substance containing the agent (as described in U.S. Patent No. 4,806,356); and the 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 formulation of buccal adhesive, when applied to the buccal mucosa, allows controlled release of the pharmacological agent in the mouth and through the buccal mucosa. The anti-inflammatory agents of the present invention can be incorporated into these formulations equally.

Aerosol Formulations For delivery to the nasal or bronchial membranes, an aerosol formulation is typically employed. The term "aerosol" includes any suspended fas, which carries gas, of the pharmacological agent, which is capable of being inhaled in the bronchi or the nasal passage. Specifically, the aerosol includes a suspension that carries droplet gas of the compounds of the present invention, as can be produced in a metered dose inhaler or a nebulizer, or a mist spray. The aerosol also includes a dry powder composition of a compound of the pharmacological agent suspended in the air another carrier gas, which can be delivered by insufflation from an inhaler device, for example. For the solutions used in the manufacture of aerosols, the preferred concentration range of the pharmacological agent is 0.1 to 100 milligrams (mg) / milliliter (ml), more preferably 0.1 to 30 mg / ml and especially preferred 1-10 mg / ml. Usually, the solutions are regulated with a compatible buffer, such as phosphate or bicarbonate. The usual pH range is from 5 to 9, preferably from 6.5 to 7.8 and more preferably from 7.-0 to 7.6. Typically, sodium chloride is added to adjust the osmolarity to the physiological range, preferably within 10% of the isotonic. The formulation of such solutions for creating aerosol inhalants is discussed in Remington's Pharmaceutical Sciences, see also Generton and Jones, DRUG DELIVERY TO THE RESPIRATORY TRACE, Ellis Horwood (1987); Gonad (1990) Critique Review in Therapeutic Drug Carrier Systems 6: 273-313; and Raeburn et al (1992) J. Pharmacol, Toxicol. Methods 27: 143-159. The pharmacological agent solutions can be converted into aerosols by any of the known resources, routinely used to obtain pharmaceutical aerosol inhalants. In general, these methods comprise pressurizing or supplying a pressurization resource to a solution container, usually with an inert carrier gas, and passing the pressurized gas through a small orifice, thereby pushing the droplets of the solution into the mouth and trachea of the animal to which the drug is to be administered. Typically, a buccal piece adapts to the entrance of the hole to facilitate delivery into the mouth or trachea.

Parenteral Formulations In yet another embodiment, the invention provides pharmaceutical compositions suitable for parenteral administration, which are provided in the form of unit doses comprising per unit dose an inhibitor of phosphodiesterase, a cyclic nucleotide analogue, or a β-adrenergic agonist, and a pharmaceutically acceptable carrier. Such compositions are useful in treating disorders and anorectal conditions, as described above. Topical Systemic Formulations Aqueous solutions and suspensions are the most widely used pharmaceutical forms to administer drugs that must be active on the surface of the eye or inside the eye, after passage through the conjunctive cornea. To increase the bioavailability of drugs, to extend therapeutic efficacy, and to improve patient acceptance, several dosage forms have been developed over the years. They include soluble inserts (which undergo gradual dissolution or surface erosion), insoluble inserts (for example, medical contact lenses, such as Ocuser®, etc.), gels (for example Gelrite®), liposomal delivery and of the drug by means of nanoparticles (emulsion, suspension, etc.) and ointments (see Edman, BIOPHARMACEUTICS OF OCULAR DRUG DELIVERY, CRC Press, 1993).

Methods of Treatment of Anorectal Disorders In another aspect, the present invention provides methods for the treatment of 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 that needs such treatment. an effective amount of any of the compositions provided above. By the use of such methods of the invention, the anorectal hypertonicity and / or the spasms are relieved and the signs and symptoms associated with the anorectal disorders, eg, anal fissures, anale and hemorrhoid ulcers, and pain, are improved. The methods described herein are also applicable to the treatment of recurrent anal diseases and are also useful to relax the anal sphincter and reduce pain during anorectal examinations (in patients with and without disorders), particularly during the procedures where instruments are inserted into the anus. . The present invention also provides methods for using the above compositions 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 the treatment of spasms and / or hypertonicity of the sphincters, which include the internal anal sphincter, the sphincter of the lower esophagus, the pyloric sphincter, sphincter of Oddi, and the ileocolic sphincter. These pharmaceutical preparations are also useful in treating conditions resulting from spasms and / or hypertonicity of the sphincters of the anorectal region, which include anal fissures, post-operative rectal pain, hypertrophic pyloric stenosis, and pancreatitis, as well as the conditions that result from the general spasm of the muscles of the Gl tract including the Zenkers diverticulum, achalasia, spasm of the esophagus (nutcracker esophagus), irritable bowel disease, and Hirschsprung's disease (obstruction of the bowel.) In another aspect, the present invention provides methods for treating anal disorders, comprising administering an effective amount of such a composition, together with a local anesthetic agent, to a subject in need of such treatment.These compositions may be administered orally, topically or parenterally. Similarly, the invention provides methods of using the above compositions in combinations with agent s local anti-inflammatories, eg, naproxen, piroxicam, etc., in pharmaceutically acceptable dosage forms, as an effective treatment for a medical condition, such as hemorrhoidal pain and for the treatment of hypertonicity and / or spasms of the sphincters, which include the internal anal sphincter, sphincter of the lower esophagus, pyloric sphincter, sphincter of Oddi, and the ileocolic sphincter. These pharmaceutical preparations are also useful in treating conditions that result from spasms and / or hypertonicity of the sphincters of the anorectal region, which include anal fissure, post-operative rectal pain, hypertrophic pyloric stenosis and pancreatitis, as well as the resulting conditions. of the general spasm of muscles of the Gl tract, which include Zenkers diverticulum, sacchalasia, esophagus spasm (nutcracker esophagus), irritable bowel disease, and Hirchsprung's disease (bowel obstruction). In another aspect, the present invention provides methods for treating anal disorders, comprising administering an effective amount of such a composition together with a local anesthetic agent to a subject in need of such treatment. These 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 the NO donors, phosphodiesterase type V (PDE V) inhibitor, phosphodiesterase type II (PDE II) inhibitor, an inhibitor of the Nonspecific PDE, a β-adrenergic agonist, a protein kinase activator, cAMP dependent, an i-adrenergic agonist, a. superoxide anion scavenger (02 ~), an ATP-sensitive K + channel activator, an estrogen or estrogen analogue, or a smooth muscle relaxant, are administered in combination or in sequence, to provide an increased therapeutic benefit. In particular, the use of a NO donor and a second agent of those provided above, may provide less severe fever and side effects, than the effective dosages of NO donors, if used alone. More particularly, the use of a NO donor in combination with a second agent, allows the use of smaller amounts of the NO donor, to achieve the same benefit in relation to the use alone, and provides the occurrence and significantly reduced duration of pain of head.

E J E M P L O S Example 1 This example illustrates the effect of cGMP mimetics, alone and in combination with a NO donor, in a relaxation model of the internal anal sphincter (IAS) of a rat. Male Sprangue-Dawley rats (300-400 g) were anesthetized with ketamine (90 mg / kg), xylazine (9 mg / kg) was given intramuscularly and supplemented, as necessary, with 1/3 dose. Rats were restrained moderately on their backs in a heated surgical table (Harvard Apparatus) for the duration of the experiments. The diuretic effects of the anesthesia were displaced by rehydration with a saline solution through a 24-gauge angiocatheter implanted intraperitoneally (VWR, San Francisco, CA). The constriction / relaxation measurement set included a Millar catheter / transducer (1.67 mm in diameter) connected to a Digi-Med (Micro-Med) Low Pressure Analyzer for pressure measurements between -50 and 150 mm Hg. . The data was integrated and converted into waveforms with the software (program) of the Digi-Med System Integrator. Changes in blood pressure were monitored using an arterial catheter / transducer and a Digi-Med Blood Pressure Analyzer with the DMSI software. The respiratory changes were inspected using a mercury stress gauge / transducer, wound around the rat's rib cage, attached to a Digi-Med Analog Signal Analyzer together with the DMSI software. Drug delivery was achieved through two Hamilton syringes without dead space, using a PE 10 pipe, adjacent to the catheter sensor. The drugs were typically applied soon after recording the stable baseline readings. Although restricted rats have been used without anesthesia in other studies, no differences in latent anal pressures were observed after anesthesia; therefore, these studies were carried out with anesthetized rats to avoid undue distress to the animals.

The pressures of the median typical internal support sphincter of the support (IASP) varied between 30 and 60 mm of Hg in this model. The Millar catheter sensor allowed for accurate isolated recordings of the IAS. Figure 1 represents a typical waveform pattern for the latent effect of the IASP. The first 10 minutes after treatment with nitroglycerin are shown in Figure 2. Using the same experimental protocol, the effect of a cGMP mimetic, dibutyryl-cGMP, was studied. Figure 3 shows that 20 μl of a 10% solution of dibutyryl-cGMP in a saline solution, applied to an anal canal, reduces the average IASP by 45% in 2.5 hours following treatment. The average IASP in the last hour before finishing the experiment had fallen by 60%. The IAP was still reduced by 34% the following morning, indicating a potential long-term effect of the drug. A subsequent dose of 1% nitroglycerin decreased IASP by 24% for 30 minutes and 71% for the first 10 minutes following treatment. After the IASP returned to the levels before treatment, an additional dose of dibutyryl-cGMP was administered and the IAP was found to decrease by 15% in the following 3 hours and 10 minutes (see Figure 4). These results support the effect of cGMP mimetics in relaxing anal sphincter muscle tone and, more importantly, suggesting a potential benefit of using a combination of the NO donor and the cGMP mimetic, due to rapid onset of NO donor action. and the longer duration of the relaxation produced by the cGMP mimetics.

EXAMPLE 2 This example illustrates the effect of phosphodiesterase inhibitors in a relaxation model of the internal anal sphincter of the rat. Using the same experimental protocol described above, an application of 20 μl of a 5% zaprinast solution in 1-methyl-2-pyrrolidinone reduced the average IASP by 21% in 32 minutes, compared with vehicle treatment alone. The effect of phosphodiesterase inhibitors can also be increased by minimal concentrations of NO donors, such as nitroglycerin that produced a rapid onset and sustained sphincter relaxation without headache and other adverse reactions observed with high doses of donors of NO alone.

Example 3 This example illustrates the effect of a potassium channel opener (minoxidil) in the constriction / relaxation model of the internal anal sphincter of the rat.

Following the same experimental protocol, as described above, a single dose of 20 μl of a 4% solution of minoxidil in 62.5% propylene glycol resulted in a 64% reduction of the IASP in 2.5 hours, followed by treatment . The vehicle only had little effect on the IAS (see Figure 5).

EXAMPLE 4 This example illustrates a method for treating anal disorders in an individual, using inhibitors of phosphodiesterase and other agents to reduce the pain associated with disorders, including anal, acute and chronic fissures. Patients with severe anal pain and especially during and after movement of the intestines, can be treated with the following therapies: zaprinast, zaprinast and nitroglycerin, minoxidil, nitroglycerin cGMP mimetics, isoproterenol, or sildanafil, one to three times daily or as required, to effectively reduce anal rectal pain. Pain reduction (indicated by a reduction in average pain and / or pain in defecation) will be evaluated and the time for pain reduction will also be evaluated. Therapy that is effective in relieving anal pain will eventually lead to the effective resolution of these anal-rectal disorders. Additionally, drugs that can effectively prevent the recurrence of diseases and even cause minimal non-adverse reactions, such as pain of head, dizziness hypotension, will be of great therapeutic benefit.

Example 5 This example illustrates a method for treating anal disorders in an individual, which uses inhibitors of phosphodiesterase and other agents to promote anal, acute and chronic fissures. Patients with anal fissures can be treated with the following therapies: zaprinast, zaprinast nitroglycerin, minoxidil, nitroglycerin and cGMP mimetics, isoproterenol or sildenafil, one to three times daily, or as required to effectively reduce bleeding and promote healing. The resolution of the disease, indi- cated by the reduction in bleeding and / or pain, can be assessed along with the time to heal. The therapy that is effective in improving hemorrhoidal symptoms will eventually lead to the complete resolution of these anal-rectal disorders. Likewise, drugs that can effectively prevent the recurrence of diseases while causing minimal or no adverse reactions, such as headache, are of significant medical benefit.

Example 7 A composition of a base gel, comprising 1. g of salbutamol, 0.6 g of carbopol 1342 USP, 35.44 g of propylene glycol, 15.16 g of dehydrated ethanol USP, 1.16 g of isopropyl alcohol USP, 2.5% of oleic acid, triethanolamine 1N HCl to adjust the pH from 6.0 to 7.0, 0.5 of butylated hydroxytoluene NF, and 29.72 g of purified water USP. Other concentrations of salbutamol can be added in the same gel base to achieve the effective dose therapeutically; this can also be achieved by adjusting the concentration of other β-antagonists with gel-based excipients, such as oleic acid.

Example 8 An example of a topical composition comprises 0.05% sildenafil 1%, 75% (w / w) of white petrolatum USP, 4% paraffin wax (weight / weight) USP / NF, lanolin 14% (weight / weight), 2% sorbitan sesquioleate NF, and 4% propylene glycol USP, in an effective therapeutic dose to the anorectal area. Typically, 50 to 600 mg of the sildenafil ointment may be applied to the anorectal area in order to reduce the signs and / or symptoms associated with anorectal disorders, eg, anal fissures, anal ulcers, and hemorrhoidal diseases. The concentration of sildenafil or other phosphodiesterase inhibitors may vary by adjusting the ratio of sildenafil with excipients that facilitates the binding of sildenafil to local tissue, or agents that increase absorption to the afflicted tissue. Yet another example of a topical composition comprises nitroglycerin at a concentration of 0.1% sildenafil at a concentration of 0.1% may be incorporated in the same base of the ointment, as mentioned above. This composition can be applied topically to a metering device, where 50 mg to 1.5 of the dose of the composition is administered to the afflicted anorectal tissue to achieve the desired therapeutic effects. Another therapeutic regimen is to deliver afflicted patients with anorectal disorders with oral sildenafil tablets as a topical nitroglycerin ointment. These two dosage forms can be used in combinations that provide the best efficacy among these patients.

Example 9 A topical spray composition of aminotiline, comprising 0.1 to 5.0% (w / w) of aminotiline, acetylated lanolin alcohol, aloe vera, butane, cetyl acetate, hydrofluorocarbon, methylparaben, laurate of PEG-8 and polysorbate 80 in a 60 cc pump spray bottle,. The concentration of aminophylline or another non-specific phosphodiesterase inhibitor can vary between 0.5 and 5%. Other non-hydrofluorocarbon propellants may also be used in place of the hydrofluorocarbon in the current composition. This composition can be sprayed directly on the afflicted tissue one to four times daily, to achieve the relief of desired signs and / or symptoms, associated with anorectal disorders. This composition can also include menthol and benzocaine to provide immediate relief of local pain and a sedative sensation, while aminophylline provides a longer lasting relaxation of anal sphincter pressure.

Example 10 A base cream composition, comprising 2 g of prazosin hydrochloride (2.0% w / w) 54.3 g of purified USP water, 2 g of Sepigel 305, 4.5 g of Crodamol, 5.0 g of glycerin, 6.0 g of oil of sesame, 15.0 g of USP white petrolatum, 2.0 g of USP lanolin, 7.0 g of 1,3-butylene glycol, 0.2 g of methylparaben and 2.0 g of silicon HL88.

A base cream can be prepared by first mixing the aqueous and non-aqueous components separately, ie the oil phase, the components of the cream. Once the aqueous phase containing the prazosin hydrochloride was mixed well, the molten oil phase was stirred moderately into the aqueous phase to form a uniform cream base.

Example 11 Sildenafil, a specific inhibitor of type V phosphodiesterase, can be administered orally by means of a tablet, parenterally or it can be applied topically to patients diagnosed with anal, acute or chronic 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 fissures, to cause the reduction of signs or symptoms associated with anorectal disorders. For topical application, an approximate dose of 50 mg to 900 mg of the cream, measured by means of a dosing device, which contains sildenafil, at a concentration of 0.02 to 5%, can be applied to the afflicted anorectal region, using a device d application or by means of the fingers, one to four times daily, to achieve the desired therapeutic effects. Alternatively, oral and topical treatment can be used in a defined regimen to achieve the best therapeutic effects. Example 12 A phosphodiesterase inhibitor, for example aminophylline, can be given orally by a tablet, parenterally or can be applied to patients diagnosed with anal fissures or other anorectal disorders, or anal fissures, acute or chronic, in a dosage form topical, for example a cream. For topical application, approximately 50 mg to 900 mg of the cream, measured by a dose measuring device, can be applied to the afflicted anorectal region using an applicator or by the fingers, one to four times daily, to achieve therapeutic effects desired.

Example 13 A β-adrenergic agonist, for example salbutamol, can be delivered in a suppository dose form to patients diagnosed with anal fissures or other anorectal disorders, or anal fissures, acute or chronic, in a topical, example a cream. For the suppository application, approximately 300 mg to 3 g of suppository unit can be applied to the afflicted anorectal region, using an applicator or by the fingers, 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 desired therapeutic effects.

Example 14 An α-adrenergic antagonist, ie prozosin, can be applied from a topical spray to patients diagnosed with haemorrhoidal disorders, alone or in combination with a local anesthetic, for example lidocaine, or in combination with the β2-agonist. β3-adrenergic mixed, for example salbutamol or in combination with an inhibitor of PDE IV, for example, arifle (SB207499), RP73401, CDP840, rolipram and LAS31025. Prazosin can be applied directly to the afflicted area with the impellent form of the spray and can be used, as needed, to relieve local pain and hypertonicity of the anal sphincter. Finally, the application of prazosin leads to the healing of hemorrhoidal disorders.

It will be understood that the examples and modality described are illustrative only and that various modifications or changes will be suggested to the persons skilled in the art and are included within the spirit and point of view of this application and the scope of the appended claims. All publications, patents and patent applications cited, are incorporated as a reference in full for all purposes.

Claims (33)

1. CLAIMS 1. A composition for the treatment of an anorectal disorder and for controlling the pain associated therewith, said composition comprising a nitric oxide (NO) donor, in admixture with a second agent, selected from the group consisting of phosphodiesterase inhibitors. type II, type IV phosphodiesterase inhibitors, type V phosphodiesterase inhibitors, non-specific phosphodiesterase inhibitors, superoxide scavengers, β-adrenergic agonists, protein kinase activators, cyclic adenosine monophosphate-dependent, cAMP, antagonists a? -adrenergic, estrogen, activators of the K + channel, sensitive to ATP and relaxers of smooth muscles, with a pharmaceutically acceptable carrier.
2. 2. A composition, according to claim 1, wherein said NO donor is selected from the group consisting of nitroglycerin, L-arginine, SNAP, GSNO and SIN-1, and said second agent is a superoxide scavenger, selected from a group consisting of superoxide dismutase and chemical mimics of superoxide dismutase
3. 3. A composition, according to claim 1, wherein said carrier is formulated for local application.
4. 4. A composition, according to claim 1, wherein said second agent is selected from the group consisting of the inhibitors of phosphodiesterase type II, the inhibitors of phosphodiesterase type IV, the inhibitors of phosphodiesterase type V and the inhibitors of phosphodiesterase type II. non-specific phosphodiesterase.
5. 5. A composition, according to claim 1, wherein said second agent is selected from the group consisting of the β-adrenergic agonists.
6. 6. A composition, according to claim 5, wherein said β-adrenergic agonist is selected from the group consisting of the β2-adrenergic agonists and the β3-adrenergic agonists.
7. 7. A composition, according to claim 1, wherein said second agent is selected from the group consisting of activators of the K + channel, sensitive to ATP.
8. 8. A composition for the treatment of an anorectal disorder, and for controlling the pain associated therewith, said composition comprises a phosphodiesterase inhibitor and a pharmaceutically acceptable carrier.
9. 9. A composition, according to claim 8, wherein the phosphodiestera inhibitor is selected from the group consisting of the inhibitors of phosphodiesterase type II, inhibitors of phosphodiestera type IV, inhibitors of the phosphodiesterase type V inhibitors of phosphodiesterase no. specific.
10. 10. A composition, according to claim 9, further comprising an agent selected from the group consisting of β-adrenergic agonists, activators of protein kinase, dependent on cAMP, α-adrenergic antagonists, blockers of the L-type Ca 2 + channel. , estrogens, activators of the K + channel, sensitive to ATP, relaxers of smooth muscles.
11. 11. A composition for the treatment of an anorectal disorder and for controlling the pain associated therewith, said composition comprising a β-adrenergic agonist a pharmaceutically acceptable carrier.
12. 12. A composition, according to claim 11, wherein the β-adrenergic agonist is specific for a receptor isoform, selected from the group consisting of β2, β3, and combinations thereof.
13. 13. A composition, according to claim 11, wherein the β-adrenergic agonist is and isoproterenol.
14. 14. A composition, according to claim 11, further comprising an agent, selected from the group consisting of PDE inhibitors, which hydrolyze cAMP, n-specific PDE inhibitors, α-adrenergic antagonists, estrogens, channel blockers, Ca2 +, type L, activators of K + channel, sensitive to ATP, and smooth muscle relaxants.
15. 15. A composition for the treatment of an anorectal disorder, and for controlling the pain associated therewith, said composition comprises an activator of the K + channel, sensitive to ATP, and a pharmaceutically acceptable carrier.
16. 16. A composition, according to claim 15, further comprising an agent selected from the group consisting of cAMP-dependent kinase activators, estrogens, cii-adrenergic antagonists, Ca2 + channel blockers, L-type blockers, and muscle relaxants. smooth.
17. 17. A composition for the treatment of an anorectal disorder and for controlling the pain associated therewith, said composition comprising an ax-adrenergic antagonist and a pharmaceutically acceptable carrier.
18. 18. A composition, according to claim 17, wherein said composition further contains an agent selected from the group consisting of phosphodiesterase inhibitors, which hydrolyze cAMP, estrogens, and smooth muscle relaxants.
19. 19. A composition, according to claim 17, wherein said phosphodiesterase inhibitor, which hydrolyzes cAMP, is an inhibitor of type IV phosphodiesterase.
20. 20. A composition for the treatment of an anorectal disorder and for controlling the pain associated therewith, said composition comprising a protein kinase activator, dependent on cAMP, and a Ca2 + channel blocker, of type L.
21. 21. A composition for the treatment of an anorectal disorder and for controlling the pain associated therewith, said composition comprising a cyclic guanosine monophosphate-dependent protein kinase activator, cGMP, and a pharmaceutically acceptable carrier.
22. 22. A composition for the treatment of an anorectal disorder, and for controlling the pain associated therewith, said composition comprises a protein kinase activator, dependent on a non-specific cyclic nucleotide, optionally in admixture with a smooth muscle relaxant.
23. 23. A method for treating an anorectal disorder, and for controlling the pain associated therewith, this method comprises administering to a subject, in need of such treatment, a therapeutically effective amount of a NO donor, and a second agent, selected from the group of inhibitors. of phosphodiesterase, type II, phosphodiesterase inhibitors, type IV, phosphodiesterase inhibitors, type V, non-specific phosphodiesterase inhibitors, superoxide scavengers, β-adrenergic agonists, protein kinase activators, cAMP-dependent, α-adrenergic antagonists, estrogens, Ca2 + anal blockers, L-type, K + channel activators, ATP-sensitive, smooth muscle relaxants.
24. 24. A method, according to claim 23, wherein the NO donor and said second agent are administered in combination.
25. 25. A method, according to claim 23, wherein said second agent is administered before a donor of the NO.
26. 26. A method, according to claim 23, in which the anorectal disorder is an anal fissure.
27. 27. A method for treating an anorectal disorder, and for controlling the pain associated therewith, this method comprises administering to a subject, in need of such treatment, a therapeutically effective amount of a composition comprising a phosphodiesterase inhibitor.
28. 28. A method, according to claim 27, further comprising administering to said subject a second agent, selected from the group consisting of β-adrenergic agonists, protein kinase activators, cAMP-dependent, ax-adrenergic, estrogen antagonists, Ca2 + channel blockers, L-type, activators of the K + channel, sensitive to ATP, smooth muscle relaxants.
29. 29. A method for treating an anorectal disorder, and for controlling the pain associated with it, this method comprises administering to a subject, in need of treatment, a therapeutically effective amount of a composition comprising a β-adrenergic agonist.
30. 30. A method, according to claim 29, further comprising administering to said subject or second agent, selected from the group consisting of activators of protein kinase, dependent on cAMP, ai-adrenergic agonists, estrogens, Ca2 + channel blockers , L-type, activators of the K + channel, sensitive to ATP, and smooth muscle relaxants.
31. 31. A method for treating an anorectal disorder, and for controlling the pain associated with it, this method comprises administering to a subject, in need of such treatment, a therapeutically effective amount of a composition comprising a potassium channel opener, sensitive to the ATP, and an agent that promotes the relaxation of the anal sphincter, mediated by the cAMP.
32. 32. A method for treating an anorectal disorder and for controlling the pain associated therewith, this method comprises administering to a subject, in need of treatment, a therapeutically effective amount of a composition that includes a potassium channel opener where this amount, therapeutically effective, it diminishes the hypertonicity of an anal sphincter muscle of the subject.
33. 33. A method for treating an anorectal disorder and for controlling the pain associated therewith, this method comprises administering to a subject, in need of treatment, a therapeutically effective amount of a composition that includes a carrier, pharmaceutically acceptable, and an agent that increase the level of cyclic guanidine monophosphate, or cyclic adenosine monophosphate, in a tissue of an anal sphincter muscle of the subject, thereby decreasing the hypertonicity of anal sphincter muscle of said subject.