MXPA05009991A - Methods for treating lower urinary tract disorders using smooth muscle modulators and alpha-2-delta subunit calcium channel modulators - Google Patents

Abstract

A method is provided for using&agr;2? subunit calcium channel modulators or other compounds that interact with the&agr;2? calcium channel subunit in combination with one ormore compounds with smooth muscle modulatory effects to treat and/or alleviate the symptoms associated with painful and non-painful lower urinary tract disorders in normal and spinal cord injured patients. According to the present invention,&agr;2? subunit calcium channel modulators include GABA analogs (e.g. gabapentin and pregabalin), fused bicyclic or tricyclic amino acid analogs of gabapentin, and amino acid compounds. Compounds with smooth muscle modulatory effects include antimuscarinics,ß3 adrenergic agonists, spasmolytics, neurokinin receptor antagonists, bradykinin receptor antagonists, and nitric oxide donors.

Description

METHODS FOR TREATING URINARY TRACT DISORDERS UNDER USE OF SMOOTH MUSCLE MODULATORS AND CHANNEL MODULATORS CALCIUM SUBUNITY ALPHA-2-DELTA FIELD OF THE INVENTION The invention relates to methods of using calcium channel modulators cx2d subunit, including analogs of GABA (eg, gabapentin and pregabalin), bicyclic or fused tricyclic amino acids analogs of gabapentin, amino acid compounds and other compounds that interact with the a2d calcium channel subunit, in combination with smooth muscle modulators to treat and / or relieve symptoms associated with painful and non-painful urinary tract disorders in patients with the spinal cord normal and injured. BACKGROUND OF THE INVENTION Low urinary tract disorders affect the quality of life of millions of men and women in the United States each year. Lower urinary tract disorders include supra-active bladder, prostatitis and prostadynia, interstitial cystitis, benign prostatic hyperplasia and associated irritative or obstructive symptoms and, in patients with injured spinal cord, spastic bladder. Supraactive bladder is a treatable medical condition that is estimated to affect 17 to 20 million people in the United States. Current treatments for the supra-active bladder include medication, diet modification, programs in bladder training, electrical stimulation and surgery. Currently, antimuscarinics (which are subtypes of the general class of anticholinergics) are the primary medication used for the treatment of the supra-active bladder. This treatment suffers from limited efficacy and side effects such as dry mouth, dry eyes, dry vagina, palpitations, drowsiness and constipation, which have proven difficult to tolerate for some individuals. In recent years, it has been recognized among those skilled in the art that OAB can be divided into urgency without any demonstrable loss of urine as well as urgency with loss of urine. For example, a recent study examined the impact of all OAB symptoms on the quality of life of a community-based sample of the United States population. (Liberman et al. (2001) Urology 57: 1044-1050). This study showed that the group of individuals suffering from OAB without any demonstrable loss of urine have an impaired quality of life when compared to controls.

Additionally, individuals with urgency only have an impaired quality of life compared to controls. Prostatitis and prostadynia are other disorders of the lower urinary tract that have been suggested to affect approximately 2-9% of the adult male population (Collins M M., et al. (1998) J. ürology, 159: 1224-1228). Currently, there are no established treatments for prostatitis and prostadynia. Antibiotics are frequently prescribed, but with little evidence of efficacy. Selective COX-2 inhibitors and α-adrenergic blockers have been suggested as treatments, but their efficacy has not been established. Hot sitz baths and anticholinergic drugs have also been used to provide some symptomatic relief. Interstitial cystitis is another disorder of the lower urinary tract of unknown etiology that predominantly affects young and middle-aged women, although men and boys may also be affected. Past treatments for interstitial cystitis have included the administration of antihistamines, sodium pentosanpolysulfate, dimethylsulfoxide, steroids, tricyclic antidepressants and narcotic antagonists, although these methods have generally been unsuccessful (Sant, GR (1989) Interstitial cystitis: pathophysiology, clinical evaluation and treatment, Urology Annal 3: 171-196). Benign prostatic hyperplasia (BPH) is a non-malignant enlargement of the prostate that is very common in men over 40 years of age. Irritative symptoms of benign prostatic hyperplasia include urinary urgency, urinary frequency and nocturia. Obstructive symptoms associated with benign prostatic hyperplasia include reduced urinary force and flow velocity. Invasive treatments for BPH include transurethral resection of the prostate, transurethral incision of the prostate, balloon dilatation of the prostate, prostate stents, microwave therapy, laser prostatectomy, high-intensity transrectal focused ultrasound therapy, and needle ablation transurethral of the prostate. However, complications can arise through the use of some of these treatments, including retrograde ejaculation, impotence, postoperative urinary tract infection and some urinary incontinence. Non-invasive treatments for BPH include androgen deprivation therapy and the use of • 5a reductase inhibitors and α-adrenergic blockers. However, these treatments have been proven effective only minimally to moderately for some patients. Low urinary tract disorders are particularly problematic for individuals suffering from spinal cord injury. After the spinal cord injury, the bladder is usually affected in one of two ways: 1) "spastic" or "reflex" bladder, in which the bladder is filled with urine and a reflex automatically activates the bladder to be emptied; or 2) "flaccid" or "non-reflex" bladder, in which the reflexes of the bladder muscles are absent or diminished. Treatment options for these disorders usually include intermittent catheterization, resident catheterization or condom catheterization, but these methods are invasive and often inconvenient. The urinary sphincter muscles can also be affected by spinal cord injuries, resulting in an inability of the urinary sphincter muscles to relax when the bladder contracts ("dissinergia"). Traditional treatments for the dissynergy include medications that have been somewhat inconsistent in their efficacy or surgery. Because existing therapies and treatments for lower urinary tract disorders and associated irritative symptoms in patients with normal and injured spinal cord have limited efficacy and are associated with side effects resulting in reduced compliance of the patient, the present invention It has a significant advantage over these treatments through increased efficacy and reduced side effects. Because the detrimental side effects are lessened, the present invention also has the benefit of improving patient compliance. BRIEF DESCRIPTION OF THE INVENTION Compositions and methods are provided for treating and / or alleviating the symptoms associated with painful and non-painful urinary tract disorders in patients with normal and injured spinal cord. The compositions of the invention comprise calcium channel modulators a2d subunit in combination with one or more compounds with modulating smooth muscle effects. In accordance with the present invention, the calcium channel modulators subunit 2d include analogs of GABA (eg, gabapentin and pregabalin), bicyclic or tricyclic amino acids fused analogues of gabapentin and amino acid compounds. Compounds with smooth muscle modulating effects include antimuscarinics, β3 adrenergic agonists, spasmolytics, neurokinin receptor antagonists, bradykinin receptor antagonists, and nitric oxide donors. The compositions of the invention include combinations of the compounds mentioned above as well as pharmaceutically acceptable, pharmacologically active, active acids, salts, esters, amides, prodrugs, active metabolites, and other derivatives thereof. The compositions are administered in therapeutically effective amounts to a patient in need thereof for treating and / or alleviating the symptoms associated with painful and non-painful urinary tract disorders, in patients with normal and injured spinal cord. It is recognized that the compositions can be administered by any means of administration as long as an effective amount is delivered to treat and / or alleviate the symptoms associated with the painful and non-painful symptoms associated with low urinary tract disorders in patients with the spinal cord. normal and injured. The compositions may be formulated, for example, for sustained, continuous administration or as necessary. An advantage of the present invention is that at least one deleterious side effect associated with the individual administration of a calcium channel modulator subunit OI25 or smooth muscle modulator is decreased by the concurrent administration of a calcium channel modulator a2d subunit with a modulator of smooth muscle. When a modulator of the calcium channel subunit is administered in combination with a modulator of smooth muscle, less than every other person is needed to achieve therapeutic efficacy. Because current treatments for painful and non-painful urinary tract disorders have limited efficacy and are associated with side effects resulting in reduced compliance of the patient, the present invention presents a significant advantage over these treatments via increased efficacy and reduced side effects.

Because the detrimental side effects are lessened, the present invention also has the benefit of improving patient compliance. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1. Figure 1 represents the effect of cumulative increased doses of oxybutynin (n = 13), gabapentin (n = ll) and their corresponding combinations (for example the Dose 1 for the combination was 30 mg / kg gabapentin and 1 mg / kg oxybutynin; n = ll) on the capacity of the bladder. The data are normalized to saline controls and are represented as Mean ± SEM. Figure 2. Figure 2 depicts the effect of cumulative increased doses of oxybutynin (n = 13), gabapentin (n = ll) and their corresponding combinations (eg, dose 1 for the combination was 30 mg / kg gabapentin and 1 mg / kg of oxybutynin, n = ll) on the capacity of the bladder (normalized to% Recovery from Irritation). The data are presented as Mean ± SEM. Figure 3. Figure 3 represents the results of isobologram studies as determined by using the means of the groups to determine effective doses. The maximum common effect for any drug alone was a return to 43% of saline control. The line that connects the two axes in the effective dose of each drug only represents the theoretical additivity.

Figure 4. Figure 4 represents the results of the isobologram studies using a maximum common effect of individual animals using a return to 31% of the saline control values. The data are presented as Mean ± SD. Figure 5. Figure 5 depicts the effect of cumulative increased doses of oxybutynin (n = 13), pregabalin (n = 7) and corresponding combinations (eg, Dose 1 for the combination was 10 mg / kg pregabalin and 1 mg / kg of oxybutynin, n = 9) on the capacity of the bladder. The data normalize to saline controls and are presented as Mean ± SEM. Figure ß. Figure 6 depicts the effect of cumulative increased doses of oxybutynin (n = 13), pregabalin (n = 7) and corresponding combinations (e.g. 1 for the combination was 10 mg / kg of pregabalin and 1 mg / kg of oxybutynin; n = 9) on the capacity of the bladder (Normalized to% Recovery from Irritation). Figure 7. Figure 7 depicts the effect of cumulative increased doses of oxybutynin (n = 13), pregabalin (n = 7) and corresponding combinations (for example, the Dosage 1 for the combination was 3.75 mg / kg of pregabalin and 0.625 mg / kg of oxybutynin; n = 4) on the capacity of the bladder.

The data are normalized to saline controls and are presented as Mean ± SEM.

Figure 8. Figure 8 depicts the effect of cumulative increased doses of oxybutynin (n = 4), pregabalin (n = 7) and corresponding combinations (eg, Dose 1 for the combination was 3.75 mg / kg of pregabalin and 0.625 mg / kg of oxybutynin, n = 4) on the capacity of the bladder (normalized to% Recovery from Irritation). The data are presented as Mean ± SEM. • Figure 9. Figure 9 depicts the effect of cumulative increased doses of tolterodine (n = 9), gabapentin (n = ll) and the two combinations tested (for example, Dose 1 for combination 1 was 30 mg / kg of gabapentin and 3 mg / kg of tolterodine, n = 4 and 3 for 3 and 10 mg / kg of tolterodine, respectively) on the capacity of the bladder. The data are normalized to saline controls and are presented as Mean ± SEM. Figure 10. Figure 10 depicts the effect of cumulative increased doses of tolterodine (n = 9), gabapentin (n = ll) and the 2 combinations (eg, Dose 1 for the combination was 30 mg / kg gabapentin and 3 mg / kg of tolterodine, n = 4 and 3, for 3 mg / kg and 10 mg / kg of tolterodine, respectively) on bladder capacity (normalized to% Recovery from Irritation). Figure 11. Figure 11 depicts the effect of cumulative increased doses of tolterodine (n = 9), pregabalin (n = 7) and their corresponding combinations (eg, Dose 1 for the combination was 10 mg / kg of pregabalin and 1 mg / kg tolterodine; n = 9) on the capacity of the bladder. The data are normalized to the saline controls and are presented as Mean ± SEM. Figure 12. Figure 12 depicts the effect of cumulative increased doses of tolterodine (n = 9), pregabalin (n = 7) and corresponding combinations (eg, Dose 1 for the combination was 10 mg / kg pregabalin and 1 mg / kg of tolterodine, n = 9) on the capacity of the bladder (normalized to% Recovery from Irritation). Figure 13. Figure 13 depicts the effect of cumulative increased doses of propiverine (n = 7), gabapentin (n = ll) and their corresponding combinations (e.g., Dose 1 for the combination was 10 mg / kg gabapentin and 3 mg / kg of propiverine, n = 10) on the capacity of the bladder. The data are normalized to saline controls and are presented as Mean ± SEM. Figure 14. Figure 14 depicts the effect of cumulative increased doses of propiverine (n = 7), gabapentin (n = ll) and their corresponding combinations (eg, Dose 1 for the combination was 10 mg / kg of gabapentin and 3 mg / kg of propiverine, n = 10) on the capacity of the bladder (normalized to% of Irritation Recovery). The data are presented as Mean ± SEM.

Figure 15. Figure 15 depicts the effect of cumulative increased doses of solifenacin (n = 4), gabapentin (n = ll) and their corresponding combinations (e.g., Dose 1 for the combination was 10 mg / kg gabapentin and 3 mg / kg of solifenacin, n = 12) on the capacity of the bladder. The data are normalized to saline controls and are presented as Mean ± SEM. Figure 16. Figure 16 depicts the effect of cumulative increased doses of solifenacin (n = 4), gabapentin (n = ll) and their corresponding combinations (e.g., Dose 1 for the combination was 10 mg / kg gabapentin and 3 mg / kg of solifenacin, n = 12) on bladder capacity (normalized to% Irritation Control). The data are presented as Mean ± SEM. Figure 17. Figure 17 depicts the effect of cumulative increased doses of oxybutynin (n = 5), gabapentin (n = 5) and their corresponding combinations (N = 6) on bladder capacity. The data are normalized to saline controls and are presented as Mean ± SEM. Figure 18. Figure 18 represents the theoretical additive effect of cumulative increased doses of oxybutynin (n = 5) and gabapentin (n = 5) and their corresponding combinations (eg, Dose 1 for the combination was 3 mg / kg of gabapentin and 0.1 mg / kg of oxitutinin, n = 6) on the capacity of the bladder (normalized to% Recovery from Irritation). The data are presented as Mean ± SEM. Figure 19. Figure 19 depicts the effect of cumulative increased doses of oxybutynin (n = 5, Figure 19A), gabapentin (n = 5, Figure 19B) on evacuation efficiency. Figure 20. Figure 20 depicts the effect of cumulative increased doses of xibutinin and gabapentin in combination (n = 6) on evacuation efficiency. Figure 21. Figure 21 depicts the effect of cumulative increased doses of the combination of oxybutynin and gabapentin (eg, Dose 1 for the combination was 30 mg / kg gabapentin and 1 mg / kg oxitutinin, n = 3) on the capacity of the bladder in chronic SCI rats. The data is normalized to vehicle controls and is presented as Mean ± SEM. Figure 22. Figure 22 depicts a dose-dependent decrease in bladder instability, as measured by a decrease in the number of evacuation contractions greater than 8 cm H20 with increased doses of the combination of oxybutynin and gabapentin (n = 3). The data are presented as Mean ± SEM. Figure 23. Figure 23 represents a dose-dependent decrease in bladder instability, as measured by the latency to the occurrence of contractions without evacuation with increased doses of the combination of oxybutynin and gabapentin (n = 3). The data is presented as Media + SEM. DETAILED DESCRIPTION OF THE INVENTION Review and Definitions The present invention provides compositions and methods for treating and / or alleviating symptoms associated with painful and non-painful urinary tract disorders in patients with normal and injured spinal cord. The disorders of the lower urinary tract of the present invention include, but are not limited to, such disorders as painful and non-painful supra-active bladder, prostatitis and prostadynia, interstitial cystitis, benign prostatic hyperplasia, and, in patients with the injured spinal cord, spastic bladder. . The irritative symptoms of these disorders include at least one symptom selected from the group consisting of urinary urgency, urinary frequency and nocturia. The compositions comprise a therapeutically effective dose of a calcium channel modulator subunit or: __ d, including gabapentin and pregabalin, in combination with one or more compounds with smooth muscle modulating effects, including antimuscarinics (particularly those that do not have an amine embedded in them). a skeleton of 8-azabicyclo [3.2.1] octan-3-ol), β3 adrenergic agonists, spasmolytics, neurokinin receptor antagonists, bradykin receptor antagonists and nitric oxide donors. The methods are carried out by administering, for example, various compositions and formulations containing amounts of a calcium channel modulator a2d subunit and / or other compounds that interact with calcium channels containing a2d subunit in combination with one or more compounds with modulating effects of smooth muscle. It is to be understood that the inventions are not to be limited to the specific embodiments disclosed and that modifications and other embodiments are proposed to be included within the scope of the appended claims. Although specific terms are used herein, they are used in a generic and descriptive sense only and not for purposes of limitation. It should be noted that as used in this specification and the attached modalities, the singular forms "a", "an" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, the reference to "an active agent" or "a pharmacologically active agent" includes an individual active agent as well as two or more different active agents in combination, the reference to "a carrier" includes mixtures of two or more carriers as well as a single carrier, and the like. By "non-painful" are proposed sensations or symptoms that include mild or general discomfort that a patient subjectively describes as not producing or resulting in pain. Such symptoms may vary depending on the disorder being treated, but generally include urinary urgency, incontinence, hurried incontinence, stress incontinence, urinary frequency, nocturia and the like. For benign prostatic hyperplasia, non-painful irritative symptoms include urinary frequency, urgency, and nocturia, while non-painful obstructive symptoms include reduced urinary force and flow velocity. By "painful" are proposed sensations or symptoms that a patient sub- tively describes as producing or resulting in pain. By "lower or lower urinary tract" all parts of the urinary system except the kidneys are proposed. By "low urinary tract disorder" any disorder involving the lower urinary tract is proposed, including, but not limited to, supra-active bladder, prostatitis, interstitial cystitis, benign prostatic hyperplasia, and spastic and flaccid bladder. By "low non-painful urinary tract disorder" any low urinary tract disorder is proposed that involves sensations or symptoms, including mild or general discomfort, that a patient subjectively describes as not producing or resulting in pain.

By "low painful urinary tract disorder" any disorder of the lower urinary tract is proposed that involves sensations or symptoms that a patient subjectively describes as producing or resulting in pain. By "disorder of the bladder" any condition that involves the urinary bladder is proposed. By "non-painful bladder disorder" any bladder disorder involving sensations or symptoms, including mild or general discomfort, which a patient subjectively describes as not producing or resulting in pain, is proposed. By "painful bladder disorder" any disorder of the bladder is proposed that involves sensations or symptoms that a patient subjectively describes as producing or resulting in pain. By "supra-active bladder" or "OAB" is proposed any form of urinary tract disorder under incontinence characterized by increased frequency of micturition or the desire to evacuate, if complete or episodic, and where the loss of voluntary control varies from partial to total and if there is loss of urine (incontinence) or there is not. By "non-painful supra-active bladder" any form of supra-active bladder is proposed, as defined in the foregoing, which involves sensations or symptoms, including mild or general discomfort, which a patient subjectively describes as not producing or resulting in pain. Non-painful symptoms may include, but are not limited to, urinary urgency, incontinence, hurried incontinence, stress incontinence, urinary frequency, and nocturia. "Wet OAB" is used herein to describe the supra-active bladder in patients with incontinence, whereas "dry OAB" is used herein to describe the supra-active bladder in patients without incontinence. Due to "urinary urgency" a sudden strong urge to urinate with little or no opportunity to postpone urination is proposed. By "incontinence" is proposed the inability to control excretory functions, including urination (urinary incontinence). By "hurried incontinence" or "hurried urinary incontinence" is proposed the involuntary loss of urine associated with an abrupt and strong desire to evacuate. By "stress incontinence" or "urinary stress incontinence" a medical condition is proposed in which urine is expelled when a person coughs, sneezes, laughs, exercises, lifts heavy objects or anything that puts pressure on the bladder. By "urinary frequency" urination is proposed more frequently than what the patient wants. As there is a considerable interpersonal variation in the number of times in a day that an individual would normally wait to urinate, "more frequently than what the patient wants" is also defined as a number of times as many times per day as the line of historical basis of the patient. "Historical baseline" is also defined as the average number of times the patient urinated per day for a normal or desirable period of time. By "nocturia" it is proposed that he is awakened from sleep to urinate more frequently than the patient wishes. By "neurogenic bladder" or "neurogenic supra-active bladder" the supra-active bladder is proposed as described herein, which is presented as the result of neurological damage due to disorders, including but not limited to stroke, Parkinson's disease, diabetes , multiple sclerosis, peripheral neuropathy or spinal cord injuries. By "detrusor hyperreflexia" a condition characterized by the non-inhibited detrusor is proposed, where the patient has some kind of neurological deterioration. By "detrusor instability" or "unstable detrusor" conditions are proposed where there is no neurological abnormality. By "prostatitis" any type of disorder associated with an inflammation of the prostate is proposed, including chronic bacterial prostatitis and chronic non-bacterial prostatitis. By "non-painful prostatitis" is proposed prostatitis that involves sensations and symptoms, including mild or general discomfort, which a patient subjectively describes as not producing or causing pain. By "painful prostatitis" is proposed prostatitis that involves sensations or symptoms, which a patient subjectively describes as producing or resulting in pain. "Chronic bacterial prostatitis" is used in its conventional sense to refer to a disorder associated with symptoms that include inflammation of the prostate and positive bacterial cultures of the urine and prostatic secretions. "Chronic nonbacterial prostatitis" is used in its conventional sense to refer to a disorder associated with symptoms that include inflammation of the prostate and negative bacterial cultures of the urine and prostatic secretions. "Prostadinia" is used in its conventional sense to refer to a disorder generally associated with painful symptoms of chronic nonbacterial prostatitis as defined above, without inflammation of the prostate. "Interstitial cystitis" is used in its conventional sense to refer to a disorder associated with symptoms that include symptoms of irritative evacuation, urinary frequency, urgency, nocturia and suprapubic or pelvic pain related to, and relieved by evacuation. "Benign prostatic hyperplasia" is used in its conventional sense to refer to a disorder associated with the benign enlargement of the prostate gland.

By "irritative symptoms of benign prostatic hyperplasia" urinary urgency, urinary frequency and nocturia are proposed. By "obstructive symptoms of benign prostatic hyperplasia" reduced urinary force and flow velocity are proposed. "Spastic bladder" or "reflex bladder" is used in its conventional sense to refer to a condition after spinal cord injury in which the emptying of the bladder has become unpredictable. "Flaccid bladder" or "non-reflex bladder" are used in their conventional sense to refer to a condition after the spinal cord injury in which the reflexes of the bladder muscles are absent or slow. "Dissinergia" is used in its conventional sense to refer to a condition after spinal cord injury in which patients are characterized by an inability of the urinary sphincter muscles to relax when the bladder contracts. By "irritative symptoms", at least one symptom selected from the group consisting of urinary urgency, incontinence, hurried incontinence, urinary frequency, nocturia is usually proposed. By "irritative symptoms of benign prostatic hyperplasia" urinary urgency, urinary frequency and nocturia are proposed. The terms "active agent" and "pharmacologically active agent" are used interchangeably herein to refer to a chemical compound that induces a desired effect, i.e., in this case, the treatment and / or relief of symptoms associated with disorders. of the urinary tract under painful and non-painful and associated irritative symptoms in patients with normal and injured spinal cord. The primary active agents herein are the modulators of the calcium channel subunit a2d and / or smooth muscle relaxants. The present invention comprises a combination therapy wherein a modulator of the calcium channel subunit a_d is administered with one or more modulators of the smooth muscle. Such a combination therapy can be carried out by the administration of the different active agents in a single composition, by the concurrent administration of the different active agents in different compositions, or by the sequential administration of the different active agents. The combination therapy may also include situations where the calcium channel modulator 2d subunit or the smooth muscle modulator is already being administered to the patient, and the additional component is going to be added to the patient's drug regimen, as well as where different individuals (for example, doctors or other medical professionals) are administering the separate components of the combination to the patient. Included are the derivatives and analogues of those compounds or classes of compounds specifically mentioned that also induce the desired effect. The term "calcium channel modulator subunit oi2d" as used herein, refers to an agent that is capable of interacting with the oi2d subunit of a calcium channel, including a binding event, including subtypes of the subunit of the calcium channel. calcium channel a_.d as it is disclosed in Klugbauer et al. (1999) J. Neurosci. 19: 684-691, to produce a physiological effect, such as opening, closing, blocking, up-regulation of functional expression, down-regulation of functional expression, or desensitization, of the channel. Unless otherwise indicated, the term "calcium channel modulator subunit o2d" is proposed to include GABA analogues (eg gabapentin and pregabalin) bicyclic or tricyclic amino acids fused analogues of gabapentin, amino acid compounds and others compounds that interact with the calcium channel subunit a2d, as is further disclosed herein, as well as acids, salts, esters, amides, prodrugs, active metabolites and other derivatives thereof. furtherIt is understood that any of the salts, esters, amides, prodrugs, active metabolites or other derivatives are pharmaceutically acceptable as well as pharmacologically active. The term "peptidomimetic" is used in its conventional sense to refer to a molecule that mimics the biological activity of a peptide, but is no longer peptidic in the chemical nature, including molecules lacking amide bonds between amino acids, as well as pseudo-peptides, semi-peptides and peptoids. The peptidomimetics according to this invention provide a spatial arrangement of reactive chemical moieties that closely resemble a three-dimensional arrangement of active groups in the peptide on which the peptide mimetic is based. As a result of the similar active site geometry, the peptidomimetic has effects on biological systems that are similar to the biological activity of the peptide. The term "smooth muscle modulator" as used herein refers to any compound that inhibits or blocks the contraction of smooth muscles, including but not limited to antimuscarinics, β3 adrenergic agonists, spasmolytics, neurokinin receptor antagonists, receptor antagonists. of bradi uinin, and nitric oxide donors. Modulators of smooth muscle can be "direct" (also known as "musculotropic") or "indirect" (also known as "neurotropic"). "Direct smooth muscle modulators" are smooth muscle modulators that act by inhibiting or blocking contractile mechanisms within smooth muscle, including but not limited to modifying the interaction between actin and myosin. "Indirect smooth muscle modulators" are modulators of smooth muscle that act by inhibiting or blocking neurotransmission resulting in contraction of smooth muscle, including but not limited to blocking presynaptic facilitation of acetylcholine release in the terminal axon. of the motor neurons that end in the smooth muscle. The term "anticholinergic agent" as used herein refers to any acetylcholine receptor antagonist, including nicotinic and muscarinic acetylcholine receptor antagonists. The term "antinicotinic agent" as used herein, is proposed for any nicotinic acetylcholine receptor antagonist. The term "anti-uscarinic agent" as used herein is intended for any antagonist to the muscarinic acetylcholine receptor. Unless otherwise indicated, the terms "anticholinergic agent", "antinicotinic agent" and "antimuscarinic agent" are proposed to include anticholinergic, antinicotinic and antimuscarinic agents as further disclosed herein, as well as acids, salts, esters , amides, prodrugs and active metabolites and other derivatives thereof. Furthermore, it is understood that any of the salts, esters, amides, prodrugs, active metabolites or other derivatives are pharmaceutically acceptable as well as pharmacologically active. The term "β3 adrenergic agonist" is used in its conventional sense to refer to a compound that binds and agonizes to β3 adrenergic receptors. Unless otherwise indicated, the term "β3-adrenergic agonist" is proposed to include β3-adrenergic agonist agents as is further disclosed herein, as well as acids, salts, esters, amides, prodrugs, active metabolites and other derivatives of the same. Furthermore, it is understood that any of the salts, esters, amides, prodrugs, active metabolites or other derivatives are pharmaceutically acceptable as well as pharmacologically active. The term "spasmolytic" (also known as "antispasmodic") is used in its conventional sense to refer to a compound that relieves or prevents muscle spasms, especially of smooth muscle. Unless otherwise indicated, the term "spasmolytic" is proposed to include spasmolytic agents as is further disclosed herein, as well as acids, salts, esters, amides, prodrugs, active metabolites and other derivatives thereof. Furthermore, it is understood that any of the salts, esters, amides, prodrugs, active metabolites or other derivatives are pharmaceutically acceptable as well as pharmacologically active. The term "neurokinin receptor antagonist" is used in its conventional sense to refer to a compound that binds to and antagonizes neurokinin receptors. Unless otherwise indicated, the term "neuroquinine receptor antagonist" is intended to include neuroquinine receptor antagonist agents as is further disclosed herein, as well as acids, salts, esters, amides, prodrugs, active metabolites, and others. derived from them. Furthermore, it is understood that any of the salts, esters, amides, prodrugs, active metabolites or other derivatives are pharmaceutically acceptable as well as pharmacologically active. The term "bradykinin receptor antagonist" is used in its conventional sense to refer to a compound that binds to and antagonizes bradykinin receptors. Unless otherwise indicated the term "bradykinin receptor antagonist" is proposed to include bradykinin receptor antagonist agents as further disclosed herein, as well as acids, salts, esters, amides, prodrugs, active metabolites or other derivatives thereof. Furthermore, it is understood that any of the salts, esters, amides, prodrugs, active metabolites or other derivatives are pharmaceutically acceptable as well as pharmacologically active. The term "nitric oxide donor" is used in its conventional sense to refer to a compound that releases free nitric oxide when administered in patients. Unless otherwise indicated, the term "nitric oxide donor" is intended to include nitric oxide donor agents as is further disclosed herein, as well as acids, salts, esters, amides, prodrugs, active metabolites or other derived from them. Furthermore, it is understood that any of the salts, esters, amides, prodrugs, active metabolites or other derivatives are pharmaceutically acceptable as well as pharmacologically active. The terms "treat" and "treatment" as used herein refer to the relief of painful or non-painful (including irritative) symptoms or other clinically observed sequelae to clinically diagnosed disorders as described herein, including disorders associated with low urinary tract in patients with normal and injured spinal cord. For an "effective" or a "therapeutically effective amount" of a pharmacologically active drug or agent a non-toxic but sufficient amount of the drug or agent is proposed to provide the desired effect, i.e., relieving the painful or non-painful symptoms associated with disorders of the lower urinary tract in patients with normal and injured spinal cord, as explained in the above. It is recognized that the effective amount of a drug or pharmacologically active agent will vary depending on the route of administration, the compound selected, and the species to which the drug or pharmacologically active agent is administered, as well as the age, weight and sex of the drug. individual to which the drug or pharmacologically active agent is administered. It is also recognized that one aspect in the art will determine the appropriate effective amounts by taking into account such factors as metabolism, bioavailability and other factors that affect the levels in the plasma of a drug or pharmacologically active agent after administration within the ranges of unit doses disclosed herein for different administration routes. By "pharmaceutically acceptable" such as in the recitation of a "pharmaceutically acceptable carrier" or a "pharmaceutically acceptable acid addition salt" a material is proposed which is not biologically or otherwise undesirable, i.e., the material can be incorporated into a pharmaceutical composition administered to a patient without causing any of the undesirable biological effects or interacting in a detrimental manner with any of the other components of the composition in which it is contained. "Pharmacologically active" (or simply "active") as in a derivative or "pharmacologically active" metabolite refers to a derivative or metabolite having the same type of pharmacological activity as the parent compound. When the term "pharmaceutically acceptable" is used to refer to a derivative (eg, a salt or an analogue) of an active agent, it is to be understood that the compound is pharmacologically active as well, ie, therapeutically effective for the treatment and / or relief of symptoms associated with painful and non-painful urinary tract disorders in patients with normal and injured spinal cord. By "continuous" dosing, the chronic administration of a selected active agent is proposed. By dosing "as necessary", also known as pro-nata dosage "" prn "and dosing or" on demand "administration, it is proposed to administer a single dose of the active agent at some time before the start of an activity where the suppression of painful and non-painful symptoms of a low urinary tract disorder in patients with normal and injured spinal cord would be desirable.Administration can be immediately before such activity including approximately 0 minutes, approximately 10 minutes, approximately 20 minutes , about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours or about 10 hours, before such activity, Depending on the formulation, any period of time is proposed for "short term" or up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes after the administration of the drug. By "quick compensation" any time period of up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 hours is proposed. minutes, approximately 20 minutes or approximately 10 minutes after the administration of the drug. The term "controlled release" is intended to refer to any drug-containing formulation in which the release of the drug is immediate, ie, with a "controlled release" formulation, oral administration does not result in the immediate release of the drug. in an accumulation of absorption. The term is used interchangeably with "non-immediate release" as defined in Remington: The Science and Practice of Pharmacy, Twenty-first Ed. (Philadelphia, Pa: 'Lippincott Williams &; Wilkins, 2000). The "absorption accumulation" represents a solution of the drug administered to a particular absorption site, and kr, ka and ke are first order rate constants for: 1) drug release from the formulation; 2) absorption; and 3) elimination, respectively. For immediate release dosage forms, the rate constant for drug release kr is much larger than the absorption rate constant ka. For controlled release formulations, the opposite is true, ie, kr < «Ka, such that the rate of release of the drug from the dosage form is the limiting step of the rate at which the drug is delivered to the target area. The term "controlled release" as used herein includes any immediate release formulation, including, but not limited to, sustained release, delayed release and pulsatile release formulations. The term "sustained release" is used in its conventional sense to refer to a drug formulation that provides for the gradual release of a drug over a prolonged period of time, and that preferably, but not necessarily, results in levels of blood drug substantially constant for a prolonged period of time such as up to about 72 hours, about 66 hours, about 60 hours, about 54 hours, about 48 hours, about 42 hours, about 36 hours, about 30 hours, about 24 hours , about 18 hours, about 12 hours, about 10 hours, about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, or about 1 hour after administration of the drug The term "delayed release" is used in its conventional sense to refer to a drug formulation that provides an initial release of the drug after some delay following the administration of the drug and that preferably, but not necessarily, includes a delay. up to about 10 minutes, about 20 minutes, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours or about 12 hours. The term "pulsatile release" is used in its conventional sense to refer to a drug formulation that provides for the release of the drug in such a manner to produce drug profiles in the pulsed plasma after administration of the drug. The term "immediate release" is used in its conventional sense to refer to a drug formulation that provides for the release of the drug immediately after administration of the drug. By the term "transdermal" drug delivery, delivery is proposed by passage of a drug through the skin or mucosal tissue and into the blood stream. The term "topical administration" is used in its conventional sense to mean the delivery of a topical drug or pharmacologically active agent to the skin or mucosa. The term "oral administration" is used in its conventional sense to mean the delivery of a drug through the mouth and ingestion through the stomach and digestive tract. The term "administration by inhalation" is used in its conventional sense to mean the delivery of an aerosolized form of the drug by passage through the nose or mouth during inhalation and the passage of the drug through the walls of the patient. lungs The term "intravesical administration" is used in its conventional sense to imply the supply of a drug directly to the bladder. By the term "parenteral" drug delivery, delivery is proposed by passage of a drug into the blood stream without first having to pass through the alimentary canal or digestive tract. The parenteral drug delivery may be "subcutaneous" with reference to the delivery of a drug by administration under the skin. Another form of parenteral drug delivery is the "intramuscular", with reference to the supply of a drug by administration to muscle tissue. Another form of parenteral drug delivery is "intradermal", with reference to the delivery of a drug by administration to the skin. An additional form of parenteral drug delivery is "intravenous" which refers to the delivery of a drug by administration to a vein. An additional form of parenteral drug delivery is "intraarterial" which refers to the delivery of a drug by administration in an artery. Another form of parenteral drug delivery is "transdermal" which refers to the delivery of a drug by passage of the drug through the skin and into the blood stream. Another form of drug delivery is "intrathecal", which refers to the delivery of a drug directly into the intrathecal space (where the fluid 'flows around the spinal cord). Yet another form of parenteral drug delivery is "transmucosal" which refers to the administration of a drug to the mucosal surface of an individual so that the drug passes through the mucosal tissue and into the bloodstream of the individual. The transmucosal drug delivery can be "buccal" or "trans-oral", which refers to the delivery of a drug by passage through a buccal mucosa of the individual and into the bloodstream. Another form of a transmucosal drug delivery herein is the "lingual" drug delivery, which refers to the delivery of a drug by passage of a drug through the individual's lingual mucosa and bloodstream. Another form of transmucosal drug delivery herein is the "sublingual" drug delivery which refers to the delivery of a drug by passage of a drug through a sublingual mucosa of the individual and into the bloodstream. Another form of transmucosal drug delivery is the "nasal" or "intranasal" drug delivery, which refers to the delivery of a drug through the individual's nasal mucosa and into the blood stream. A further form of transmucosal drug delivery herein is the "rectal" or "transrectal" drug delivery, which refers to the delivery of a drug, by passage of a drug through the rectal mucosa of an individual already the bloodstream. Another form of transmucosal drug delivery is the "urethral" or "transurethral" delivery which refers to the delivery of the drug to the urethra such that the drug contacts and passes through the wall of the urethra. In a further form of transmucosal drug delivery is the "vaginal" or "transvaginal" delivery, which refers to the delivery of a drug by passage of a drug through the vaginal mucosa of an individual and into the bloodstream. An additional form of the trnasmucosal drug supply is the "periviphal" delivery, which refers to the delivery of a drug through the vaginolabial tissue and into the blood stream. In order to carry out the method of the invention, a selected active agent is administered to a patient suffering from a painful or non-painful urinary tract disorder or associated irritative symptoms in patients with normal and injured spinal cord. A therapeutically effective amount of the active agent can be administered orally, intravenously, subcutaneously, transmucosally (including buccally, sublingually, transurethrally and rectally), topically, transdermally, by inhalation, intravesically, intrathecally or the use of any other route of administration. Urinary Tract Disorders Under The compositions and methods of the invention are useful for treating disorders of the lower urinary tract that affect the quality of life of millions of men and women in the United States each year. While the kidneys filter the blood and produce urine, the baho urinary tract is related to the storage and disposal of this waste fluid and includes all other parts of the urinary tract except the kidneys. Generally, the lower urinary tract includes the ureters, the urinary bladder and the urethra. Low urinary tract disorders include painful and non-painful supra-active bladder, prostatitis and prostadynia, interstitial cystitis, benign prostatic hyperplasia, and in patients injured in the spinal cord, spastic bladder and flaccid bladder. Supraactive bladder is a treatable medical condition that is estimated to affect 17 to 20 million people in the United States. Symptoms of the supra-active bladder include urinary frequency, urgency, nocturia (disturbed sleep at night due to the need to urinate) and hurried incontinence (accidental loss of urine) due to a sudden and non-stop need to urinate. As opposed to stress incontinence, in which the loss of urine is associated with physical actions such as coughing, sneezing, exercising or the like, hurried incontinence is usually associated with a supra-active detrusor muscle (the smooth muscle of the bladder that contracts and causes it to empty). There is no unique etiology for the supra-active bladder. Neurogenic overactive bladder (or neurogenic bladder) presents with the result of neurological damage due to disorders such as stroke, Parkinson's disease, diabetes, multiple sclerosis, peripheral neuropathy or spinal cord injuries. In these cases, the detrusor muscle supraactivity is called detrusor hyperreflexia. In contrast, non-neurogenic supraactive bladder can result from non-neurological abnormalities including bladder stones, muscle disease, urinary tract infection, or side effects from drugs. Due to the enormous complexity of micturition (the act of urination) the exact mechanism that causes the supra-active bladder is unknown. The supra-active bladder can result from the hypersensitivity of the sensory neurons of the urinary bladder, which arise from several factors including inflammatory conditions, hormonal imbalances and hypertrophy of the prostate. The destruction of sensory nerve fibers, either from a crush injury to the sacral region of the spinal cord, from a disease that causes damage to the dorsal root fibers as they enter the spinal cord can also lead to the supra-active bladder . In addition, damage to the spinal cord or brainstem that causes the interruption of the transmitted signals can lead to abnormalities in micturition. Therefore, both peripheral and central mechanisms may be involved in mediating altered activity in the supra-active bladder. Despite the uncertainty that considers whether central or peripheral mechanisms, or both, are involved in the supra-active bladder, many proposed mechanisms involve neurons and pathways that mediate non-painful visceral sensation. Pain is the perception of an aversive or unpleasant sensation and can arise through a variety of proposed mechanisms. These mechanisms include the activation of specialized sensory receptors that provide information about tissue damage (nociceptive pain), or through nerve damage from diseases such as diabetes, trauma or toxic doses of drug (neuropathic pain) (See, for example, AI Basbaum and TM Jessell (2000) The Perception of Pain, In Principies of Neural Sciende, 4th ed.: Benevento et al. (2002) Physical Therapy Journal 82: 601-12). Nociception can give rise to pain, but not all stimuli that activate nociceptors are experienced as pain (A. I. Basbaum and T.M. Jessel (2000) The perception of pain, In Principles of Neural Science, 4th ed.). The somatosensory information of the bladder is transmitted by the nociceptive Ad and C fibers that enter the spinal cord via the dorsal root ganglia (DRG) and project to the brainstem and thalamus via the neurons of the brain. second or third order (Andersson (2002) ürology 59: 18-24; Andersson (2002) ürology 59: 43-50; Morrison, J., Steers, WD, "Brading, A., Blok, B., Fry, C, Groat, WC, Kakizaki, H., Levin, R., and Thor, KB," Basic Urological Sciences "In : Incontinent (vol.2) Abrams, P. Khoury, S., and Wein, A. (Eds.) Health Publications, Ltd., Plumbridge Distributors, Ltd., Plymounth, UK., (2002) .A number of different subtypes of sensory afferent neurons may be involved in neurotransmission from the lower urinary tract.These may be classified as, but not limited to, small diameter, medium diameter, large diameter, myelinated, non-myelinated, sacral, lumbar, peptidegic, non-peptidergic, IB4 positive, IB4 negative, C fiber, Ad fiber, high threshold or low threshold The nociceptive entry to DRG is thought to be transported to the brain along several ascending pathways, including spinothalamic, spinoreticular, espinomesenfálica, espinocervical and in some cases the tracts of the dorsal / medial lemniscal column (A. Basbaum and T.M. Jessel (2000) The perception of pain. In Principies of Neural Science 4a. ed.). The central mechanisms, which are not fully understood, are thought to convert some, but not all, nociceptive information into painful sensory perception (AI Basbaum and TM Jessell (2000), The Perception of Pain, in Principies of Neural Sciende, 4th ed. .). Current treatments for the supra-active bladder include medication, diet modification, bladder training programs, electrical stimulation and surgery. Currently the antimuscarinics, which are subtypes of the general class of anticholinergics (a primary medication used for the treatment of the supra-active bladder.) This treatment suffers from limited efficacy and side effects such as dry mouth, dry eyes, dry vagina, palpitations, drowsiness and constipation, which have been proven difficult to tolerate for some individuals.Although many compounds have been explored as treatments for disorders involving bladder pain or other pelvic visceral organs, relatively little work has been directed towards the treatment of non-painful sensory symptoms associated with bladder disorders such as the supra-active bladder.The current treatments for supra-active bladder include medication, diet modification, bladder training programs, electrical simulation and surgery.Today, antimuscarinics (which are subtypes of the general class of anticholinergics) are the primary medication used for the treatment of the supra-active bladder. This treatment suffers from limited efficacy and side effects such as dry mouth, dry eyes, dry vagina, palpitations, drowsiness and constipation, which have proven difficult to tolerate for some individuals. The supra-active bladder (or OAB) can occur with or without incontinence. In recent years, it has been recognized among those skilled in the art that the cardinal symptom of OAB is urgency without considering any demonstrable loss of urine. For example, a recent study examined the impact of all OAB symptoms on the quality of life of a population-based sample of the United States population (Liberman et al. (2001) ürology 57: 1044-1050). This study demonstrated that individuals suffering from OAB without any demonstrable loss of urine have a deteriorated quality of life when compared to controls. Additionally, individuals with urgency only have an impaired quality of life compared to controls. Although urgency is now believed to be the primary symptom of OAB, to date it has not been evaluated in a quantified manner in clinical studies. Corresponding to this new understanding of the OAB, however, the terms of the Wet OAB (with incontinence) and Dry OAB (without incontinence) have been proposed to describe these different patient populations (see, for example, WO 03/051354) . The prevalence of wet OAB and dry OAB is reported to be similar in men and women, with a prevalence rate in the United States of 16.6% (Stewart et al., "Prevalence of Overactive Bladder in the United States: Results from the NOBLE Program. "Abstract Presented at the Second International Consultation on Incontinent, July 2001, Paris, France). Prostatitis and prostadynia are other disorders of the lower urinary tract that have been suggested to affect approximately 2-9% of the adult male population (Collins MM, et al. (12998) "How common is prostatitis? A national survey of physician visits," Journal of Urology, 159: 1224-1228). Prostatitis is associated with an inflammation of the prostate, and can be subdivided into chronic bacterial prostatitis and chronic non-bacterial prostatitis. Chronic bacterial prostatitis is thought to arise from the bacterial infection that is generally associated with such symptoms as inflammation of the prostate, the presence of white blood cells in the prostatic fluid and / or pain. Chronic nonbacterial prostatitis is an inflammatory and painful condition of unknown etiology characterized by excessive inflammatory cells in prostatic secretions despite a lack of documented urinary tract infections and negative bacterial cultures of urine and prostatic secretions. Prostadynia (chronic pelvic pain syndrome) is a condition associated with the painful symptoms of chronic non-bacterial prostatitis without an inflammation of the prostate. Currently, there are no established treatments for prostatitis and prostadynia. Antibiotics are frequently prescribed, but with little evidence of efficacy. Selective COX-2 inhibitors and a-adrenergic blockers have been suggested as treatments but their efficacy has not been established. Hot sitz baths and anticholinergic drugs have also been used to provide some symptomatic relief. Interstitial cystitis is another disorder of the lower urinary tract of unknown etiology that predominantly affects young and middle-aged women, although men and boys may also be affected. Symptoms of interstitial cystitis may include irritative evacuation symptoms, urinary frequency, urgency, nocturia and suprapubic or pelvic pain related to, and relieved by evacuation. Many patients with interstitial cystitis also experience headaches as well as gastrointestinal and skin problems. In some extreme cases, interstitial cystitis can also be associated with ulcers or bladder injuries. Past treatments for interstitial cystitis have included the administration of antihistamines, sodium pentosanpolysulfate, dimethylsulfoxide, steroids, tricyclic antidepressants and narcotic antagonists, although these methods have generally been unsuccessful (Sant, GR (1989) Interstitial cystitis: pathophysiology, clinical evaluation and treatment. ology Annal 3: 171-196). Benign prostatic hyperplasia (BPH) is a non-malignant enlargement of the prostate that is very common in men over 40 years of age. BPH is thought to be due to excessive cell growth of both glandular and stromal elements of the prostate. Irritative symptoms of benign prostatic hyperplasia include urinary urgency, urinary frequency and nocturia. The obstructive symptoms associated with benign prostatic hyperplasia are characterized by reduced urinary strength and flow velocity. Invasive treatments for BPH include transurethral resection of the prostate, transurethral incision of the prostate, balloon dilatation of the prostate, prostate stents, microwave therapy, laser prostatectomy, high-intensity transrectal focused ultrasound therapy, and needle ablation transurethral of the prostate. However, complications can arise through the use of some of these treatments, including retrograde ejaculation, impotence, postoperative urinary tract infection and some urinary incontinence. Non-invasive treatments for BPH include androgen deprivation therapy and the use of 5a reductase inhibitors and α-adrenergic blockers. However, these treatments have been proven effective only minimally to moderately for some patients. Low urinary tract disorders are particularly problematic for individuals suffering from spinal cord injury. After injury to the spinal cord, the kidneys continue to produce urine, and urine can continue to flow through the ureters and urethra because they undergo involuntary neural and muscle control, with the exception of conditions where it is present the dissinergia of the bladder to the smooth muscle. In contrast, the bladder and sphincter muscles also undergo voluntary muscular and neural control, which means that the descending input of the brain through the spinal cord induces the bladder and sphincter muscles to completely empty the bladder. After the spinal cord injury, such descending entry can be interrupted such that individuals can no longer have voluntary control of their bladder and sphincter muscles. Spinal cord injuries can also interrupt sensory signals that ascend to the brain, preventing such individuals from being able to feel the urge to urinate when their bladder is full. The compositions and methods of the invention find use in alleviating or reducing the irritative symptoms and / or obstructive symptoms of benign prostatic hyperplasia and may reduce the need for other, more invasive treatments. After the spinal cord injury, the bladder is usually affected in one of two ways. The first is a condition called "spastic" or "reflex" bladder, in which the bladder is filled with urine and an automatically active reflex to empty the bladder. This usually occurs when the injury is above level T12. Individuals with spastic bladder are unable to determine when, or if, the bladder will be varied. The second is the "flaccid" or "non-reflex" bladder in which the reflexes of the bladder muscles are absent or slow. This only occurs when the injury is below level T12 / L1. Individuals with flaccid bladder may experience bladders over extended or stretched and "reflux" of urine through the ureters in the kidneys. Treatment options for these disorders usually include intermittent catheterization, resident catheterization or condom catheterization, but these methods are invasive and often inconvenient. The urinary sphincter muscles can also be affected by spinal cord injury, resulting in a condition known as "dissinergia". The dissinergia involves an inability of the urinary sphincter muscles to relax when the bladder contracts, including active contraction in response to contraction of the bladder, which prevents the urine from flowing through the urethra and results in the incomplete emptying of the bladder and "reflux" of the urine to the kidneys. Traditional treatments for dissynergy include medications that have been somewhat inconsistent in their effectiveness or surgery. Peripheral Effects Against Centrals The mammalian nervous system comprises a central nervous system (CNS), which comprises the brain and the spinal cord) and a peripheral nervous system (PNS, comprising sympathetic, parasympathetic, sensory, motor and enteric neurons outside the brain and spinal cord). Where an active agent according to the present invention is proposed to act centrally (i.e. exeits effects via the action on neurons in the CNS), the active agent must either be administered directly to the CNS or be capable of to deviate or cross the blood-brain barrier. The blood-brain barrier is a capillary wall structure that effectively screens all selected categories of substances present in the blood, preventing its passage to the CNS. The unique morphological characteristics of the cerebral capillaries that constitute the blood-brain barrier are: 1) high-strength hermetic joints similar to the epithelium that literally glue the entire endothelium of the cerebral capillaries together within the regions of the blood-brain barrier of the CNS and 2) pinocytosis scanty or transendothelial channels, which are abundant in the endothelium of peripheral organs. Due to the unique characteristics of the blood-brain barrier, hydrophilic drugs and peptides that readily gain access to other tissues in the body are ensured entry to the brain or their input rates are very low. The blood-brain barrier can be effectively deviated by direct infusion of the active agent into the brain, or by intranasal administration and inhalation of formulations suitable for uptake and retrograde transport of the active agent by olfactory neurons. The most common procedure for administration directly into the CNS is the implantation of a catheter into the ventricular system or the intrathecal space. Alternatively, the active agent can be modified to increase its transport through the blood-brain barrier. This generally requires some solubility of the drug in lipids, or other appropriate modification known to one skilled in the art. For example, the active agent can be truncated, derivatized, latentiated (converted from a hydrophilic drug into a lipid-soluble drug) conjugated to a lipophilic moiety or a substance that is actively transported through the blood-brain barrier, or modified using standard means known to those skilled in the art. See, for example, Pardridge, Endocrine Reviews 7: 314-330 (1986) and the North American patent No. 4,801,575. Where an active agent according to the present invention is intended to act exclusively peripherally (i.e., exeits effects via the action of either on the neurons in the PNS or directly on the target tissues), it may be It is desirable to modify the compounds of the present invention in such a way that they will not pass the blood-brain barrier. The principle of the permeability of the blood-brain barrier can therefore be used to design active agents with selective potency for peripheral purposes. Generally, a drug insoluble in lipid will not cross the blood-brain barrier, and will not produce effects on the CNS. A basic drug acting on the nervous system can be altered to produce a selective peripheral effect by quaternizing the drug, which decreases its lipid solubility and makes it virtually unavailable for transfer to the CNS. For example, the antimuscarinic drug, metscopalamin bromide has peripheral effects while the scopolamine of the uncharged antimuscarinic drug acts centrally. One skilled in the art can select and modify active agents of the present invention using the standard chemical synthetic techniques well known for adding a lipid-impermeable functional group such as a quaternary amine, sulfate, carboxylate, phosphate or sulfonium to prevent transport to through the blood-brain barrier. Such modifications are by no means the only way in which the active agents of the present invention can be modified to be impervious to the blood-brain barrier.; other well known pharmaceutical techniques exist and would be considered to fall within the scope of the present invention. Agents The compounds useful in the present invention include any active agent as defined elsewhere herein. Such active agents include, for example, calcium channel modulators a2d subunit, including GABA analogs (e.g., gabapentin and pregabalin), as described elsewhere herein, as well as smooth muscle modulators, including antimuscarinics, adrenergic agonists. β3, spasmolytics, neurokinin receptor antagonists, bradykinin receptor antagonists and nitric oxide donors, as described elsewhere herein. Voltage-gated calcium channels, also known as voltage-gated calcium channels, are mui-subunit membrane extension proteins that allow the influx of calcium controlled from an extracellular environment into a cell. The opening and closing (commanded) of calcium channels controlled by voltage is controlled by a region sensitive to the voltage of the protein that contains charged amino acids that move within an electric field. The movement of these charged groups leads to conformational changes in the structure of the channel that result in conducive (open / activated) or non-conductive (closed / inactivated) states. Voltage-gated calcium channels are present in a variety of tissues and are involved in several life processes in animals. Changes in the influx of calcium in the cell mediated through these calcium channels has been implicated in several human diseases such as epilepsy, stroke, brain trauma, Alzheimer's disease, multi-infarct dementia, other kinds of dementia , Korsakoff's disease, neuropathy caused by a viral infection of the brain or spinal cord (eg, human immunodeficiency virus, etc.), amyotrophic lateral sclerosis, seizures, seizures, Huntington's disease, amnesia or damage to the nervous system that results of the supply of reduced oxygen, poisoning or other toxic substances (See, for example, U.S. Patent No. 5,312,928). Voltage-gated calcium channels have been classified by their electrophysiological and pharmacological properties as types T, L, N, P and Q (for reviews see McCleskey et al. (1991) Curr. Topics Membr. 39: 295-326; and Dumlap and collaborators (1995) Trains, Neurosci 18: 89-98). Because there is some overlap in the biophysical properties of high voltage activated channels, pharmacological profiles are useful to further distinguish them. The L-type channels are sensitive to dihydropyridine agonists and antagonists. The N-type channels are blocked by the peptide? -conotoxin GVIA, a peptide toxin from the conical shell mollusk, Comis geographus. The P-type channels are blocked by the peptide? -agatoxin IVA from the venom of the funnel web spider, Agelenopsis asperta. A fourth type of high voltage activated calcium channel (type Q) has been described, although if Q and P type channels are distinct molecular entities it is controversial (Sather-et al. (1995) Neuron 11: 291-303; Stea and collaborators (1994) Proc. Nati, Acad Sci USA 91: 10576-10580, Bourinet et al. (1999) Nature Neuroscience 2: 407-415). Voltage-regulated calcium channels are mainly defined by the combination of different subunits; a_, a2, ß,? and d (see Caterall (2000) Annu., Rev. Cell. Dev. Biol. 16: 521-55). Ten types of subunits oc_, four a2d complexes, four subunits ß and subunits? they are known (see Caterall, Annu, Rev. Cell, Dev. Biol., supra, see also Klugbauer et al., (1999) J. Neurosci., 19: 684-691). Based on the combination of different subunits, calcium channels can be divided into three structurally and functionally related families: Cavl, Cav2 and Cav3 (for reviews, see Caterall, Annu, Rev. Cell, Dev. Biol., Supra).; Ertel et al., (2000) Neuron 25: 533-55). L-type currents are mediated by a Cavl family of ai subunits (see Caterall, Annu, Rev. Cell, Dev Biol., Supra). The Cav2 channels form a distinct family with an amino acid sequence identity of less than 40% with the Cavla_ subunits (see Caterall, Annu, Rev. Cell, Dev. Biol., Supra). Cloned Cav2.1 subunits lead P- or Q-type currents that are inhibited by? -agatoxins IVA (see Caterall, Annu., Rev. Cell, Dev. Biol., Supra, Sather et al., (1993) Neuron 11: 291 -303; Stea et al., (1994) Proc. Nati, Acad. Sci. USA 91: 10576-80; Bourinet et al., (1999) Nat. Neurosci. 2: 407-15). The Cav2.2 subunits drive the N-type calcium currents and have a high affinity for the? -conotoxin GVIA,? -conotoxin MVIIA and synthetic versions of these peptides including Ziconotide (see Caterall, Annu.

Cell. Dev. Biol. , supra; Dubel et al., (1992) Proc.

Nati Acad. Sci. USA 89: 5058-62; Williams and collaborators, (1992) Science 257: 389-95). The cloned Cav2.3 subunits lead a current of calcium known as type R and are resistant to specific organic antagonists for the L-type calcium currents and the specific peptide toxins for the N or P / Q currents ((see Caterall, Annu, Rev. Cell, Dev. Biol., Supra, Randall et al., (1995) J. Neurosci 15: 2995-3012, Soong et al., (1994) Science 260: 1133-36, Zhang et al. (1993) Neuropharmacology 32: 1075-88) Gamma-aminobutyric acid analogues (GABA) are compounds that are derived from or based on GABA GABA analogs are either available or easily synthesized using known methodologies for those Those skilled in the art Exemplary GABA analogs include gabapentin and pregabalin.Gabapentin (Neurontin, or 1- (aminomethyl) -cyclohexaneacetic acid) is an anticonvulsant drug with a high binding affinity for some subunits of the calcium channel, and is It is represented by the following structure: Gabapentin is one of a series of compounds of the formula: H2N-CH2-p-CH2-COORt (CH2) n wherein R_ is hydrogen or a lower alkyl radical and n is 4, 5 or 6. Although gabapentin was further developed as a mimetic GABA compound to treat spasticity, gabapentin has no direct GABAergic action and does not block the uptake or metabolism of GABA (For review, see Rose et al., (2002) Analgesia 57: 451-462). However, gabapentin has been found to be an effective treatment for the prevention of partial seizures in patients who are refractory to other anticonvulsant agents (Chadwick (1991) Gabapentin, In Pedley TA, Meldrum BS (eds.), Recent Advances in Epilepsy , Churchill Livingstone, New York, pages 211-222). Gabapentin and the related drug pregabalin interact with the a2d subunit of calcium channels (Gee et al., (1996) J. Biol. Chem. 271: 5768-5776). In addition to its known anticonvulsant effects, gabapentin has been shown to block the tonic phase of nociception induced by formalin and carrageenan and exerts an inhibitory effect on neuropathic pain models of mechanical hyperalgesia and mechanical / thermal allodynia (Rose et al. 2002) Analgesia 57: 451-462). Double-blind, placebo-controlled experiments have indicated that gabapentin is an effective treatment for painful symptoms associated with diabetic peripheral neuropathy, post-herpetic neuralgia, and neuropathic pain (see, for example, Backonja et al., (1998) JAMA 280 : 1831-1836; Mellegers et al., (2001) Cliva. J Pain 17: 284-95). Pregabalin, (S) - (3-aminomethyl) -5-methylhexanoic acid or (S) -isobutyl GABA, is another GABA analogue whose use as an anticonvulsant has been explored (Bryans et al., (1998) J. Med. Chem 41: 1838-1845). Pregabalin has been shown to still possess higher binding affinity for the a2d subunit of calcium channels than gabapentin (Bryans et al., (1999) Med. Res. Rev. 19: 149-177). Exemplary GABA analogs and fused bicyclic or tricyclic amino acids of gabapentin analogs that are useful in the present invention include: 1. Gabapentin or salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites or derivatives thereof; 2. Pregabalin or salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites or derivatives thereof; 3. GABA analogs according to the following structure as described in US Pat. No. 4,024,175 or salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites or derivatives thereof, H2N-CH2-C-CH2- COOR. (CH2) n wherein R_ is hydrogen or a lower alkyl radical and n is 4, 5 or 6; GABA analogs in accordance with the following structure as described in U.S. Patent No. 5,563,175 or salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites or derivatives thereof, wherein i is a linear or branched alkyl group having from 1 to 6 carbon atoms, phenyl or cycloalkyl having from 3 to 6 carbon atoms; R2 is hydrogen or methyl; and R3 is hydrogen, methyl or carboxyl; 5. Substituted amino acids in accordance with the following structures as described in U.S. Patent No. 6,316,638 or salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites or derivatives thereof, wherein R_a Rio are each independently selected from hydrogen or a linear or branched alkyl of 1 to 6 carbons, benzyl or phenyl; m is an integer from 0 to 3; n is an integer of 1 to 2; or is an integer from 0 to 3; p is an integer from 1 to 2; q is an integer from 0 to 2; r is an integer from 1 to 2; s is an integer of 1 3; t is an integer from 0 to 2; and u is an integer from 0 to 1; 6. GABA analogs as disclosed in PCT publication No. WO 93/23383 or salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites or derivatives thereof; 7. GABA analogs as disclosed in Bryans et al., (1998) J. Med. Chem. 41: 1838-1845 or salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites or derivatives thereof; 8. GABA analogs as disclosed in Bryans et al., (1999) Med. Res. Rev. 19: 149-177 or salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites or derivatives thereof; 9. Amino acid compounds according to the following structure as described in the North American application No. 20020111338 or salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites or derivatives thereof; wherein i and R2 are independently hydrogen or hydroxy; X is selected from the group consisting of hydroxy and Q2-G- where: G is -O-, -C (0) 0- or -NH-; Qx is a group derived from a linear oligopeptide comprising a first D portion and further comprises from 1 to 3 amino acids, and wherein the group is cleavable from the amino acid compound under physiological conditions; D is a portion of the GABA analogue; Z is selected from the group consisting of: (i) a substituted alkyl group containing a portion that is negatively charged at physiological pH, this portion which is selected from the group consisting of -COOH, -S03H, -S02H, -P (O) (OR16) (OH), -OP (O) (OR16) (OH), -OS03H and the like and wherein R16 is selected from the group consisting of alkyl, substituted alkyl, aryl and substituted aryl; and (ii) a group of the formula -M-Qx ', Wherein M is selected from the group consisting of -CH0C (0) - and -CH2CH2C (0) - and wherein Qx 'is a group derived from a linear oligopeptide comprising a first portion D' and further comprising 1 to 3 amino acids, and where the group is segmentable under physiological conditions; D 'is a portion of the GABA analogue; or a pharmaceutically acceptable salt thereof; with the proviso that when X is hydroxy, then Z is a group of the formula -M-Qx '; 10. Cyclic amino acid compounds as disclosed in PCT publication No. WO 99/08670 or salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites or derivatives thereof; 11. Cyclic amino acids in accordance with the following structures as disclosed in PCT Publication No. W099 / 21824 or salts, enantiomers, analogues, esters, amides, prodrugs, active metabolites or derivatives thereof, wherein R is hydrogen or a lower alkyl; Ri to R14 are each independently selected from hydrogen, linear or branched alkyl of 1 to 6 carbons, phenyl, benzyl, fluorine, chlorine, bromine, hydroxy, hydroxymethyl, amino, aminomethyl, trifluoromethyl, -C02H, -C02R__5, -CH2C02H, -CHC02Ri5, -0R_.5 wherein R_.5 is a linear or branched alkyl of 1 to 6 carbons, phenyl or benzyl and R_ to R8 are not simultaneously hydrogen; 12. Bicyclic amino acids in accordance with the following structures as disclosed in published U.S. patent application serial number No. 60/160725, including those disclosed having high activity as measured in a radioligand binding assay using [3H] gabapentin and the a2d subunit derived from porcine brain tissue or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites and derivatives thereof, and 13. Bicyclic amino acid analogs according to the following structures as disclosed in British patent application GB 2 374 595 and acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites and derivatives thereof.

OX) (X) (XD (xp) (XM) (XIV) (XV) (XVI) (XVH) (XVIII) (XIX) (XX) (XXI) (XXT) (XXII) (XXH1) (xxiv) Other useful agents in. The present invention includes any compound that binds the a2d subunit of a calcium channel. GABA analogs that exhibit binding affinity to the a2 subunit? of the calcium channels and which are therefore useful in the present invention include without limitation cis- (ÍS, 3R) - (1- (aminomethyl) -3-methylcyclohexane) acetic acid, cis- (IR, 3S) - (1- (aminomethyl) -3-methylcyclohexane) acetic acid, 3a, 5 - (1-aminomethyl) - (3,5-dimethylcyclohexane) acetic acid, (9- (aminomethyl) bicyclo [3.3.1] non- 9-yl) acetic acid and (7- (aminomethyl) bicyclo [2.2.1] hept-7-yl) acetic acid (Bryans et al., (1998) J. Med. Chem. 41: 1838-1845; Bryans et al., (1999) Med. Res. Rev. 19: 149-177). Other compounds that have been identified as calcium channel modulators include, but are not limited to, those described in U.S. Patent No. 6,316,638, U.S. Patent No. 6,492,375, U.S. Patent No. 6,294,533, U.S. Patent No. 6,011,035, U.S. Pat. No. 6,387,897, U.S. Patent No. 6,310,059, U.S. Patent No. 6,294,533, U.S. Patent No. 6,267,945, PCT Publication No. WO 01/49670, PCT Publication No. WO 01/46166, and PCT Publication No. WO 01/45709. The identification of these compounds that have a binding affinity for the a2d subunit of calcium channels can be terminated by performing the a2d binding affinity studies as described by Gee et al., (Gee et al., (1996) J. Biol. Chem. 271: 5768-5776). The identification of yet additional compounds, including other GABA analogues, that exhibit binding affinity for the a2d subunit of calcium channels can also be determined by performing a2d binding affinity studies as described by Gee et al., (Gee. et al., (1996) J. Biol.

Chem. 271: 5768-5776). In addition, compositions and formulations comprising GABA analogs and cyclic amino acid analogues of gabapentin that would be useful in the present invention include compositions disclosed in PCT Publication No. WO 99/08670, U.S. Patent No. 6,342,529, controlled release formulations. as disclosed in U.S. Application No. 20020119197 and U.S. Patent No. 5,955,103 and sustained release compounds and formulations as disclosed in PCT Publication No. WO 02/28411, PCT Publication No. WO 02/28881, publication. No. PCT No. WO 02/28883, PCT Publication No. WO 02/32376, PCT Publication No. WO 02/42414, US Application No. 20020107208, US Application No. 20020151529 and US Application No. 20020098999. Acetylcholine is A chemical neurotransmitter in the nervous system of all animals. "Cholinergic neurotransmission" refers to neurotransmission involving acetylcholine, and has been involved in the control of functions as diverse as locomotion, digestion, heart rate, "fight or momentum" responses and learning and memory (Salvaterra (Feb. 2000) Acetylcholine. Xn Encyclopedia of Life Sciences. London: Nature Publishing Group, http: / www. els .net). The acetylcholine receptors are classified into two generic categories based on the alkaloids of plants that preferentially interact with these: 1) nicotinic (nicotinic link); or 2) muscarinic (muscarinic link) (See, for example, Salvaterra, Acetylcholine, supra). The two general categories of acetylcholine receptors can also be divided into subclasses based on differences in their pharmacological and electrophysiological properties. For example, nicotinic receptors are composed of a variety of subunits that are used to identify the following subclasses: 1) nicotinic acetylcholine receptors of muscle; 2) neuronal nicotinic acetylcholine receptors that do not bind snake venom a-bungarotoxin; and 3) neuronal nicotinic acetylcholine receptors that bind snake venom a-bungarotoxin (Dani et al.

(July 1999) Nicotinic Acetylcholine Receptors in Neurons.

In Encyclopedia of Life Sciences. London: Nature Publishing Group, http: / www. els.net; Lindstrom (October 2001) Nicotinic Acetylcholine Receptors. In Encyclopedia of Life Sciences. London: Nature Publishing Group, http: / www. els.net). In contrast, muscarinic receptors can be divided into five subclasses labeled M_-M5, and preferentially coupled with specific G proteins.

(Mi, M3 and M5 with Gq; M2 and M_ with G __ / G0) (Nathanson (July 1999) Muscarinic- Acetylcholine Receptors, In Encyclopedia of Life Sciences, London: Nature Publishing Group, http: / www. . In general, muscarinic receptors have been implicated in bladder function, (See, for example, Appell (2002) Cleve, Clin. J. Med. 69: 761-9; Diouf et al., (2002) Bioorg. Med. Chem. Lett 12: 2535-9; Crandall (2001) J Womens Health Gend, Based Med. 10: 735-43; Chapple (2000) Urology 55: 33-46). Other agents useful in the present invention include any anticholinergic agent, specifically, any antimuscarinic agent. Particularly useful in the methods of the present invention is oxybutynin, also known as 4-diethylaminium-2-butynyl phenylcyclohexyglycolate. This has the following structure: Ditropan (oxybutynin chloride) is the racemic mixture of d, 1 of the above compound, which is known to exert antispasmodic effect on smooth muscle and inhibit the muscarinic action of smooth muscle acetylcholine. The metabolites and isomers of oxybutynin have also been shown to have useful activity in accordance with the present invention. Examples include, but are not limited to, N-desethyl-oxybutynin and S-oxybutynin (see, for example, U.S. Patent Nos. 5,736,577 and 5,532,278). Additional compounds that have been identified as antimuscarinic agents and are useful in the present invention include, but are not limited to: a. Darifenacin (Daryon®) or acids, salts, enantiomers, analogues, esters, amides, prodrugs, active metabolites and derivatives thereof; b. Solifenacin or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites and derivatives thereof; c. YM-905 (solifenacin succinate) or acids, salts, enantiomers, analogues, esters, amides, prodrugs, active metabolites and derivatives thereof; d. Solifenacin monohydrochloride or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites and derivatives thereof; and. Tolterodine (Detroit®) or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites and derivatives thereof; F. Propiverine (Detrunom®) or acids, salts, enantiomers, analogues, esters, amides, prodrugs, active metabolites and derivatives thereof; g. Propantheline Bromide (Pro-Banthine®) or acids, salts, enantiomers, analogues, esters, amides, prodrugs, active metabolites and derivatives thereof; h. Hyoscyamine sulfate (Levsin®, Cystospaz®) or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites and derivatives thereof; i. Dicyclomine hydrochloride (Bentyl®) or acids, salts, enantiomers, analogues, esters, amides, prodrugs, active metabolites and derivatives thereof; j. Flavoxate hydrochloride (Urispas ") or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites and derivatives thereof; k. D, 1 (racemic) 4-diethylamino-2-butynyl phenylcyclohexylglycollate or acids, salts , enantiomers, analogs, esters, amides, prodrugs, active metabolites and derivatives thereof; 1. L-hydrogen tartrate of (R) -N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropanamine or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites and derivatives thereof; m. Monosuccinate of (+) - (ÍS, 3'R) -quinuclidin-3'-lyl-1-phenyl-1,2,4,4-tetrahydroisoquinoline-2-carboxylate or acids, salts, enantiomers, analogues, esters, amides, prodrugs, active metabolites and derivatives thereof; n. Alpha (+) -4- (Dimethylamino) -3-methyl-1,2-diphenyl-2-butanol propionate or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites and derivatives thereof; or. l-methyl-4-piperidyl diphenylpropoxyacetate or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites and derivatives thereof; p. 3a-hydroxyespiro [H, 5aH-nortropan-8, 1'-pyrrolidinium benzylate or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites and derivatives thereof; q. Compounds containing 4-amino-piperidine as disclosed in Diouf et al., (2002) Bioorg. Med. Chem. Lett. 12: 2535-9; r. pirenzipine or acids, salts, enantiomers, analogues, esters, amides, prodrugs, active metabolites and derivatives thereof; s. methoctramine or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites and derivatives thereof; t. 4-diphenylacetoxy-N-methyl piperidine methylodide; or. tropicamide or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites and derivatives thereof; v. (2R) -N- [1- (6-aminopyridin-2-ylmethyl) piperidin-4-yl] -2- [(IR) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetamide or acids, salts , enantiomers, analogs, esters, amides, prodrugs, active metabolites and derivatives thereof; w. PNU-200577 ((R) -N, N-diisopropyl-3- (2-hydroxy-5-hydroxymethylphenyl) -3-phenylpropanamine) or acids, salts, enantiomers, analogues, esters, amides, prodrugs, active metabolites and derivatives of the same; x. KRP-197 (4- (2-methylimidazolyl) -2,2-diphenylbutyramide) or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites and derivatives thereof; Y. Fesoterodine or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites and derivatives thereof; and Z. SPM 7605 (the active metabolite of Fesoterodine) or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites and derivatives thereof. The identification of additional compounds having antimuscarinic activity and therefore that will be useful in the present invention is determined by carrying out muscarinic receptor binding specificity studies as described by Nilvebrant (2002) Pharmacol. Toxicol 90: 260-7 or cystometry studies as described by Modiri et al., (2002) Urology 59: 963-8. Adrenergic receptors are cell surface receptors for two major catecholamine hormones and neurotransmitters: noradrenaline and adrenaline. (Malbon et al., (February 2000) Adrenergic Receptors, Jn Encyclopedia of Life Sciences, London: Nature Publishing Group, http: / www. Els .net). Adrenergic receptors have been implicated in critical physiological processes, including control of blood pressure, smooth muscle myocardial contractility, lung function, metabolism, and central nervous system activity (See, for example, Malbon et al., Adrenergic Receptors, supra) . Two classes of adrenergic receptors are identified, a and ß, which can also be subdivided into three main families (al, a2 and ß), each with at least three subtypes (alA, B and D, a2A, B and C; , ß2 and ß3) based on their binding characteristics to different agonists and molecular cloning techniques. (See, for example, Malbon et al., Adrenergic Receptors, supra). It has been shown that ß3 adrenergic receptors are expressed in the detrusor muscle and that the detrusor muscle relaxes with a ß3 agonist (Takeda, M. et al. (1999) J. Pharmacol. Exp. Ther. 288: 1367-1373) and in general, ß3 adrenergic receptors have been implicated in bladder function (See, for example, Takeda et al., (2002) Neuourol, Urodyn, 21: 558-65; Takeda et al. (2000) J. Pharmacol. Exp. Ther. 293: 939-45. Other agents useful in the present invention include any β3 adrenergic agonist agent. Compounds that have been identified as ß3 adrenergic agonist agents and are useful in the present invention include, but are not limited to: a. TT-138 and phenylethanolamine compounds as disclosed in U.S. Patent No. 6,069,176, PCT Publication No. WO 97/15549 and available from Mitsubishi Phanna Corp., or acids, salts, esters, amides, prodrugs, active metabolites and other derivatives thereof; b. FR-149174 and propanolamine derivatives as disclosed in U.S. Patent Nos. 6,495,546 and 6,391,915 and available from Fujisawa Pharmaceutical Co., or acids, salts, esters, amides, prodrugs, active metabolites and other derivatives thereof; c. KUC-7483, available from Kissei Pharmaceutical Co., or acids, salts, esters, amides, prodrugs, active metabolites and other derivatives thereof, d. 4'-Hydroxynorephedrine derivatives such as 2-2-chloro-4- (2- ((SS, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethylamino) ethyl) -phenoxyacetic acid as disclosed in Tanaka et al., (2003) J. Med. Chem. 46: 105-12 or acids, salts, esters, amides, prodrugs, active metabolites and other derivatives thereof; and. Compounds of 2-amino-1-phenylethanol, such as BRL35135 acid methyl ester hydrobromide salt ((R * R *) - (. + -.) - [4- [2- [2- (3-chlorophenyl)) -2-idroxyethylamino] propyl] -phenoxy] acetic acid as disclosed in Japanese Patent Publication No. 26744 of 1988 and European Patent Publication No. 23385) and SR5861 1A ((RS) -N- (7- ethoxycarbonylmethoxy-1,2,3,4-tetrahydronaphth-2-yl) -2- (3-chlorophenyl) -2-hydroxyethanamine as disclosed in the patent open to the Japanese public Publication No. 66152 of 1989 and the open patent publication to the European public No. 255415) or acids, salts, esters, amides, prodrugs, active metabolites and other derivatives thereof; F. GS 332 ((2R) - [3- [3- [2- (3-chlorophenyl) -2-hydroxyethylamino] cyclohexyl] phenoxy] sodium acetate) as disclosed in Iizuka et al., (1998) J. Smooth Muscle Res. 34: 139-49 or acids, salts, esters, amides, prodrugs, active metabolites and other derivatives thereof; g. BRL-37,344 (4- [- [(2-hydroxy- (3-chlorophenyl) ethyl) -amino] propyl] phenoxyacetate) as disclosed in Tsujii et al., (1998) Physi ol. Behav. 63: 723-8 and available from GlaxoSmithKIine or acids, salts, esters, amides, prodrugs, active metabolites and other derivatives thereof; h. BRL-26830A as disclosed in Takahashi et al., (1992) Jpn Circ. J. 56: 936-42 and available from GlaxoSmithKIine or acids, salts, esters, amides, prodrugs, active metabolites and other derivatives thereof; i. CGP 12177 (4- [3-t-butylamino-2-hydroxypropoxy] benzimidazol-2-one) (a reported β1 / β2 adrenergic antagonist that acts as an agonist for the β3 adrenergic receptor) as described in Tavernier et al. ( 1992) J. Pharmacol. Exp. Ther. 263: 1083-90 and available from Ciba-Geigy or acids, salts, esters, amides, prodrugs, active metabolites and other derivatives thereof; j. CL 316243 (R, R-5- [2- [[2- (3-chlorophenyl) -2-hydroxyethyl] amino] propyl] -1,3-benzodioxol-2, 2-dicarboxylate) as disclosed in Berlan et al. , (1994) J. Pharmacol. Exp. There 268: 1444-51 or acids, salts, esters, amides, prodrugs, active metabolites and other derivatives thereof; k. Compounds having ß3 adrenergic agonist activity as disclosed in the US patent application 20030018061 or acids, salts, esters, amides, prodrugs, active metabolites and other derivatives thereof; 1. ICI 215.001 HCl ((S) -4- [2-hydroxy-3-phenoxypropylaminoethoxy] phenoxyacetic acid hydrochloride) as disclosed in Howe (1993) Drugs Future 18: 529 and available from AstraZeneca / ICI Labs or acids, salts , enantiomers, analogs, esters, amides, prodrugs, active metabolites and derivatives thereof; m. ZD 7114 HCl (ICI D7114; (S) -4- [2-Hydroxy-3-phenoxypropylaminoethoxy] -N- (2-methoxyethyl) phenoxyacetamide HCl) as disclosed in Howe (1993) Drugs Future 18: 529 and available from AstraZeneca / ICI Labs or acids, salts, enantiomers, analogues, esters, amides, prodrugs, active metabolites and derivatives thereof; n. Pindolol (1- (lH-Indol-4-yloxy) -3- [(1- ethylethyl) amino] -2-propanol) as disclosed in Blin et al., (1994) Mol. Pharmacol. 44: 1094 or acids, 'salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites and derivatives thereof; or. (S) - (-) -Pindolol ((S) -1- (lH-indol-4-yloxy) -3- [(1-methylethyl) amino] -2-propanol) as disclosed in Walter et al. ( 1984) Naunyn-Schmied. Arch. Pharmacol. 327: 159 and Kalkman (1989) Eur. J. Pharmacol. 173: 121 or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites and derivatives thereof; p. SR 59230A HCl (1- (2-Ethylphenoxy) -3- [[(1-1, 2,3,4-tetrahydro-1-naphthalenyl] amino] - (2S) -2-propanol hydrochloride) as disclosed in Manara et al., (1995) Pharmacol, Comm. 6: 253 and Manara et al., (1996) Br. J. Pharmacol. 117: 435 and available from Sanofi-Midy or acids, salts, enantiomers, analogues, esters, amides, prodrugs, active metabolites and derivatives thereof: SR 58611 (N [2s) 7-carbethoxymethoxy-1, 2,3,4-tetrahydronaphthyl] - (2r) -2-hydroxy-2 hydrochloride ( 3-chlorophenyl) etamine) as disclosed in Gauthier et al., (1999) J. Pharmacol. Exp. Ther. 290: 687-693 and available from Sanofi Research; and r. YM178 available from Yamanouchi Pharmaceutical Co. or acids, salts, esters, amides, prodrugs, active metabolites and other derivatives thereof. The identification of additional compounds having β3 adrenergic agonist activity and therefore would be useful in the present invention can be determined by performing radioligand binding assays and / or contractility studies as described by Zilberfarb et al., (1997) J. Cell Sci. 110: 801-807; Takeda et al., (1999) J. Pharmacol. Exp. Ther. 288: 1367-1373; and Gauthier et al., (1999) J. Pharmacol. Exp. Ther. 290: 687-693. Spasmolytics are compounds that relieve or prevent muscle spasms, especially of smooth muscle. In general, spasmolytics have been implicated to be effective in the treatment of bladder disorders (See, for example, Takeda et al., (2000) J. Pharmacol. Exp. Tuer. 293: 939-45). Other useful agents of the present invention include any spasmolytic agent. Compounds that have been identified as spasmolytic agents and are useful in the present invention include, but are not limited to: a. 4- (N-methyl-piperidylic) esters of α, α-diphenylacetic acid as disclosed in U.S. Patent No. 5,897,875 or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites and derivatives thereof; b. Human and porcine spasmolytic polypeptides in glycosylated form and variants thereof as disclosed in U.S. Patent No. 5,783,416 or acids, salts, enantiomers, analogues, esters, amides, prodrugs, active metabolites and derivatives thereof; c. Dioxazocine derivatives as disclosed in U.S. Patent No. 4,965,259 or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites and derivatives thereof; d. 6, 11-Dihydro-dibenzo- [b, e] -thiepin-11-N-alkylnorscopine quaternary ethers as disclosed in U.S. Patent No. 4,608,377 or acids, salts, enantiomers, analogs, esters, amides, prodrugs, metabolites assets and derivatives thereof; and. Quaternary salts of dibenzo [1,4] diazepinones, pyrido- [1,4] benzodiazepinones, pyrido [1,5] benzodiazepinones as disclosed in U.S. Patent No. 4,594,190 or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites and derivatives thereof; F. Endo-8, 8-dialkyl-8-azoniabicyclo (3.2.1) octan-6, 7-exo-epoxy-3-alkylcarboxylate salts as disclosed in U.S. Patent No. 4,558,054 or acids, salts, enantiomers, analogues, esters, amides, prodrugs, active metabolites and derivatives thereof; g. Pancreatic spasmolytic polypeptides as disclosed in US Patent No. 4,370,317 or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites and derivatives thereof; h. Triazinones as disclosed in U.S. Patent No. 4,203,983 or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites and derivatives thereof; i. 2- (4-Biphenylyl) -N- (2-diethylaminoalkyl) propionamide as disclosed in U.S. Patent No. 4,185,124 or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites and derivatives thereof; j. Piperazino-pyrimidines as disclosed in U.S. Patent No. 4,166,852 or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites and derivatives thereof; k. Aralkylamino carboxylic acids as disclosed in U.S. Patent No. 4,163,060 or acids, salts, enantiomers, analogues, esters, amides, prodrugs, active metabolites and derivatives thereof; 1. Aralkylamino sulfones as disclosed in U.S. Patent No. 4,034,103 or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites and derivatives thereof; m. Smooth muscle spasmolytic agents as disclosed in US Pat. No. 6,207,852 or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites and derivatives thereof; and n. Papaverine or acids, salts, enantiomers, analogues, esters, amides, prodrugs, active metabolites and derivatives thereof. The identification of additional compounds having spasmolytic activity and therefore would be useful in the present invention can be determined by performing bladder strip contractility studies as described in US Pat. No. 6,207,852; Noronha-Blob et al. (1991) J. Pharmacol. Exp. Ther. 256: 562-567; and / or Kachur et al., (1988) J. Pharmacol. Exp. Ther. 247: 867-872. Tachykinins (TKs) are a family of structurally related peptides that include substance P, neuroquinin A (NKA) and neuroquinin B (NKB). Neurons are the main source of TKs in the periphery. An important general effect of TKs is neuronal stimulation, but other effects include endothelium-dependent vasodilation, extravasation of plasma protein, recruitment of mast cells and degranulation and stimulation of inflammatory cells (See Maggi, CA (1991) Gen. Pharmacol ., 22: 1-24). In general, tachykinin receptors have been implicated in bladder function (See, for example, Ka oy co-workers, (2000) Eur. J. Pharmacol. 401: 235-40 and Omhura et al., (1997) Uro 1 Int. 59: 221-5).

Substance P activates the neurokinin receptor subtype referred to as NK_. Substance P is an undecapeptide that is present at sensory nerve terminals. Substance P is known to have multiple actions that produce inflammation and pain in the periphery after activation of fiber C including vasodilation, extravasation of degranulation plasma from mast cells (Levine, JD et al., (1993) J. Neurosci.13: 2273). Neuroquinin A is a peptide that is colocalized in the sensory neurons with substance P and that also promotes inflammation and pain. Neurokinin A activates the specific neurokinin receptor as NK_ (Edmonds-Alt, S. et al., (1992) Life Sci. 50: PL101). In the urinary tract, the TKs with potent spasmogens that act through only the NK2 receptor in the human bladder, as well as the human urethra and the ureter (Maggi, CA (1991) Gen. Pharmacol., 22: 1-24 ). Other useful agents of the present invention include any neurokinin receptor antagonist agent. Neurokinin receptor antagonists suitable for use in the present invention acting on the Ki receptor include, but are not limited to: 1-imino-2- (2-methoxy-phenyl) -ethyl) -7,7-diphenyl -4-perhydroisoindolone (3aR, 7aR) ("RP 67580"); 2S, 3S-cis-3- (2-methoxybenzylamino) -2-benzhydrylquinuclidine ("CP 96.345"); and (aR, 9R) -7- [3, 5-bis (trifluoromethyl) benzyl] -8, 9, 10, 11-tetrahydro-9-methyl-5- (4-methylphenyl) -7H- [1,4] diazocino [2,1-g] [1,7] naphthyridin-6,13-dione) ("TAK-637"). Neuronin receptor antagonists suitable for use in the present invention that act on the NK2 receptor include, but are not limited to: ((S) -N-methyl-N-4- (4-acetylamino-4-phenylpiperidino) -2- (3,4-dichlorophenyl) butylbenzamide ("SR 48968"); Met-Asp-Trp-Phe-Dap-Leu ("MEN 10.627"); and cyc (Gln-Trp-Phe-Gly-Leu-Met) ("L 659,877"). Neurokinin receptor antagonists suitable for use in the present invention also include acids, salts, esters, amides, prodrugs, active metabolites and other active derivatives of any of the aforementioned agents. identification of additional compounds having neuroquinine receptor antagonist activity and therefore would be useful in the present invention can be determined by performing binding assay studies as described in Hopkins et al., (1991) Biochem. Biophys. Res. Conic 180: 1110-1117; and Aharony et al., (1994) Mol. Pharmacol. 45: 9-19 The bradiquinin receptors are generally divided into bradykinin (Bi) and bradykinin2 (B2) subtypes. Studies have shown that acute peripheral pain and inflammation produced by bradykinin are mediated by subtype B2 whereas bradykinin-induced pain in the chronic inflammation arrangement is mediated by the Bi subtype pathway (Perkins, MN et al. (1993) Pain 53: 191-97); Dray, A. and collaborators, (1993) Trends Neurosci. 16: 99-104). In general, bradiquinin receptors have been implicated in the function of the bladder (See, for example, Meini et al., (2000) Eur. J. Pharmacol. 388: 177-82 and Belichard et al., (1999) Br. J. Pharmacol., 128: 213-9). Other agents useful in the present invention include any antagonist agent of the bradykinin receptor. Bradiquinin receptor antagonists suitable for use in the present invention acting on the Bi receptor include, but are not limited to: des-arg10 HOE 140 (available from Hoechst Pharmaceuticals) and des-Arg9 bradiquinin (DABK). Bradiquinin receptor antagonists suitable for use in the present invention acting on the B2 receptor include, but are not limited to: D-Phe7-BI; D-Arg- (Hyp3-Thi5'8-D-Phe7) -BK ("NPC 349"); D-Arg- (Hyp3-D-Phe7) -BK ("NPC 567"); D-Arg- (Hyp3-Thi5-D-Tic7-Oic8) -BK ("HOE 140"); H-DArg-Arg-Pro-Hyp-Gly-Thi-c (Dab-DTic-Oic-Arg) c (7gamma-10alpha) ("MEN11270"); H-DArg-Arg-Pro-Hyp-Gly-Thi-Ser-DTic-Oic-Arg-OH ("Icatibant"); (E) -3- (6-Acetamido-3-pyridyl) -N- [N- [2,4-dichloro-3- [(2-methyl-8-quinolinyl) oxymethyl] phenyl] -N-methylaminocarbonylmethyl] - acrylamide ("FR173567"); and WIN 64338. These compounds are more fully described in Perkins, M. N. et al., Painr supra; Dray, A. and collaborators, Trends Neurosci. , supra; and Meini et al., (2000) Eur. J. Pharmacol. 388: 177-82. Neuronin receptor antagonists suitable for use in the present invention also include acids, salts, esters, amides, prodrugs, active metabolites and other derivatives of any of the agents mentioned in the foregoing. The identification of additional compounds having bradykinin receptor antagonist activity and therefore would be useful in the present invention can be determined by performing the binding assay studies as described in Manning et al., (1986) J. Pharmacol. Exp. Ther. 237: 504 and U.S. Patent No. 5,686,565. Nitric oxide donors can be included in the present invention particularly for their anti-spasm activity. Nitric oxide (NO) plays a critical role as a molecular mediator of many physiological processes, including vasodilation and regulation of normal vascular tone. The action of NO is involved in local and intrinsic vasodilation mechanisms. It is NOT the smallest known biologically active molecule and is the mediator of an extraordinary range of physiological processes (Nathan (1994) Cell 78: 915-918; Thomas (1997) Neurosurg Focus 3: Article 3). NO is also a known physiological antagonist of endothelin-1, which is the most potent mammalian vasoconstrictor known to have "at least ten times the vasoconstrictive potency of angiotensin II" (Yanagisawa et al., (1988) Nature 332: 411-415; Kasuya et al., (1993) J. Neurosurg, 79: 892-898, Kobayashi et al., (1991) Neurosurgery 28: 673-679.) The biological half-life of NO is extremely short (Morris et al., (1994 ) Am. J. Physiol. 266: E829- E839; Nathan (1994) Cell 78: 915-918) It does NOT fully account for the biological effects of endothelial-derived relaxation factor (EDRF) and is an extremely potent vasodilator that it is believed that it works through the action of cGMP-dependent protein kinases to effect vasodilation (Henry et al., (1993) FASEB J. 7: 1124-1134; Nathan (1992) FASEB J. 6: 3051-3064 Palmer et al. (1987) Nature 327: 524-526; Snyder et al. (1992) Scientific American 266: 68-77). Within endothelial cells, an enzyme known as NO synthase (NOS) catalyzes the conversion of L-arginine to NO that acts as a second diffusible messenger and mediates responses in adjacent smooth muscle cells. It is NOT continuously formed and released by the vascular endothelium under basal conditions that inhibit contractions and controls the basal coronary tone and is produced in the endothelium in response to several agonists (such as acetylcholine) and other endothelium-dependent vasodilators. Thus, the regulation of NOS activity and the levels resulting from NO are key molecular targets that control vascular tone (Muramatsu et al., (1994) Coron, Artery Dis. 5: 815-820). Other agents useful in the present invention include any nitric oxide donor agent. Nitric oxide donors suitable for the practice of the present invention include, but are not limited to: a. Nitroglycerin or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites and derivatives thereof; b. Nitroprusside of sodium or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites and derivatives thereof; c. FK 409 (OR-3) or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites and derivatives thereof; d. FR 144420 (ÑOR-4) or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites and derivatives thereof; and. 3-morpholinosidnonimine or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites and derivatives thereof; F. Linsidomine hydrochloride ("SIN-1") or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites and derivatives thereof; g. S-Nitroso-N-acetylpenicillamine ("SNAP") or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites and derivatives thereof; h. AZD3582 (lead compound CINOD, available from NicOx S.A.) or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites and derivatives thereof; i. NCX 4016 (available from NicOx S.A.) or acids, salts, enantiomers, analogues, esters, amides, prodrugs, active metabolites and derivatives thereof; j. NCX 701 (available from NicOx S.A.) or acids, salts, enantiomers, analogues, esters, amides, prodrugs, active metabolites and derivatives thereof; k. NCX 1022 (available from NicOx S.A.) or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites and derivatives thereof; 1. HCT 1026 (available from NicOx S.A.) or acids, salts, enantiomers, analogues, esters, amides, prodrugs, active metabolites and derivatives thereof; m. NCX 1015 (available from NicOx S.A.) or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites and derivatives thereof; n. NCX 950 (available from NicOx S.A.) or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites and derivatives thereof; or. NCX 1000 (available from NicOx S.A.) or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites and derivatives thereof; p. NCX 1020 (available from NicOx S.A.) or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites and derivatives thereof; q. AZD 4717 (available from NicOx S.A.) or acids, salts, enantiomers, analogues, esters, amides, prodrugs, active metabolites and derivatives thereof; r. NCX 1510 / NCX 1512 (available from NicOx S.A.) or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites and derivatives thereof; s. NCX 2216 (available from NicOx S.A.) or acids, salts, enantiomers, analogues, esters, amides, prodrugs, active metabolites and derivatives thereof; t. NCX 4040 (available from NicOx S.A.) or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites and derivatives thereof; or. Nitric oxide donors as disclosed in U.S. Patent No. 5,155,137 or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites and derivatives thereof; v. Nitric oxide donors as disclosed in U.S. Patent No. 5,366,997 or acids, salts, enantiomers, analogues, esters, amides, prodrugs, active metabolites and derivatives thereof; w. Nitric oxide donors as disclosed in U.S. Patent No. 5,405,919 or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites and derivatives thereof; x. Nitric oxide donors as disclosed in U.S. Patent No. 5,650,442 or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites and derivatives thereof; Y. Nitric oxide donors as disclosed in U.S. Patent No. 5,700,830 or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites and derivatives thereof; z. Nitric oxide donors as disclosed in U.S. Patent No. 5,632,981 or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites and derivatives thereof; aa. Nitric oxide donors as disclosed in US Pat. No. 6,290,981 or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites and derivatives thereof; bb. Nitric oxide donors as disclosed in U.S. Patent No. 5,691,423 or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites and derivatives thereof; EC. Nitric oxide donors as disclosed in U.S. Patent No. 5,721,365 or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites and derivatives thereof; dd. Nitric oxide donors as disclosed in U.S. Patent No. 5,714,511 or acids, salts, enantiomers, analogues, esters, amides, prodrugs, active metabolites and derivatives thereof; ee Nitric oxide donors as disclosed in US Pat. No. 6,511,911 or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites and derivatives thereof; and ff. Nitric oxide donors as disclosed in U.S. Patent No. 5,814,666. The identification of additional compounds having nitric oxide donor activity and therefore would be useful in the present invention can be determined by the release profile and / or the induced vasospasm studies as described in U.S. Patent Nos. 6,451,337 and 6,358,536, as well as Moon (2002) IBJU Int. 89: 942-9 and Fathian-Sabet et al., (2001) J. Urol. 165: 1724-9. Enantiomers and Diasteromers Many organic compounds exist in optically active form, that is, they have the ability to rotate the plane of polarized light in the plane. In the description of an optically active compound the prefixes R and S are used to denote the absolute configuration of the molecule around its chiral center (s). The prefixes D and L, or (+) or (-), designate the sign of rotation of the polarized light in the plane by the compound, with L or (-) which means that the compound is levorotatory. In contrast, a compound with prefix D or (+) is dextrorotatory. There is no correlation between the nomenclature for absolute stereochemistry and for the rotation of an enantiomer. So, the acid, D-lactic acid is the same as acid (-) - Lactic acid and L-lactic acid is the same as (+) - lactic acid. For a given chemical structure, each of a pair of enantiomers are identical except that they are not superimposed mirror images of each other. A specific stereoisomer may also be required as an enantiomer, and a mixture of such isomers is often called an enantiomeric or racemic mixture. Stereochemical purity is important in the pharmaceutical field, where many of the most commonly prescribed drugs exhibit chirality. For example, the L-enantiomer of the beta-adrenergic blocking agent, propranolol, is known to be 100 times more potent than its D-enantiomer. Additionally, optical purity is important in the field of pharmaceutical drugs because certain isomers have been found to impact a deleterious effect, before an advantageous and inert effect, for example, is believed that the D enantiomer of thalidomide is a sedative safe and effective when prescribed for the control of morning nausea of pregnancy, while its corresponding L-enantiomer is believed to be a potent teratogen. When two chiral centers exist in a molecule, there are four possible stereoisomers: (R, R), (S, S), (R, S) and (S, R). Of these, (R, R) and (S, S) are examples of a pair of enantiomers (mirror images of each other), which typically share chemical properties and melting points very similar to any other enantiomeric pair. The mirror images of (R, R) and (S, S) are not, however, superimposable on (R, S) and (S, R). This ratio is called diastereoisomeric and the molecule (S, S) is a diastereomer of the molecule (R, S), while the molecule (R, R) is a diastereomer of the molecule (S, R). An example of a compound with two chiral centers is the antimuscarinic solifenacin. Solifenacin is described in U.S. Patent No. 6,174,896 and is represented by the following chemical formula: Because solifenacin has two chiral centers, diastereomers as well as enantiomers exist for this molecule (see U.S. Patent No. 6,174,896). Solifenacin succinate (development number YM-905) is a form of solifenacin salt that is co-promoted as Vesicare® by Yamanouchi Pharmaceutical Co., Ltd. (through Yamanouchi Pharma America) and GlaxoSmithKine as a muscarinic antagonist of research that is thought to act on the receptors in the smooth muscle of the bladder. The solifenacin was discovered and developed by Yamanouchi and a New Drug Application was sent to the U.S. Food and Drug Administration by YPA in December 2002 for solifenacin succinate. A request for market authorization to visit Vesicare was sent in Europe in January 2003 and Yamanouchi has started Phase III clinical trials for Vesicare® in Japan. Other forms of solifenacin salts have also been described specifically by Yamanouchi, including solifenacin monohydrochloride (development number YM-53705).

For use in the present invention, any diastereomer or enantiomer of an active agent as disclosed herein, can be administered to treat painful and non-painful urinary tract disorders and associated irritative symptoms in patients with normal and injured spinal cord. . Formulations The formulations of the present invention may include, but are not limited to, continuous formulations, as necessary, short term, rapid onset, controlled release, sustained release, delayed release and pulsatile release. Compositions of the invention comprise modular calcium channel subunit a2d in combination with one or more compounds with modular effects of smooth muscle, including antimuscarinics (particularly those that do not have an amine embedded in an 8-azabicyclo skeleton [3.2.1] octan-3-ol), ß3 adrenergic agonists, spasmolytics, neuroquinine receptor antagonists, bradiquinin receptor antagonists and nitric oxide donors. The compositions are administered in therapeutically effective amounts to a patient in need thereof to treat and / or alleviate symptoms associated with painful and non-painful urinary tract disorders in patients with normal and injured spinal cord. It is recognized that the compositions can be administered by any means of administration as long as an effective amount is provided to treat and / or alleviate the symptoms associated with the painful and non-painful symptoms associated with low urinary tract disorders in patients with the spinal cord. normal and injured. Any of the active agents can be administered in the form of a salt, ester, amide, prodrug, active metabolite, derivative or the like, with the proviso that the salt, ester, amide, prodrug or derivative is pharmacologically suitable, i.e. effective in the present method. The salts, esters, "amides, prodrugs and other derivatives of the active agents can be prepared using standard procedures known to those skilled in the art of synthetic organic chemistry and described, for example, by J. March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 4- Edition.

(New York: Wiley-Interscience, 1992). For example, acid addition salts are prepared from the free base using conventional methodology and involve reaction with a suitable acid. Suitable acids for preparing acid addition salts include both organic acids, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid. citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like, as well as inorganic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, acid phosphoric and the like. An acid addition salt can be converted to the free base by treatment than a suitable base. Particularly preferred acid addition salts of the active agents herein are salts prepared with organic acids. Conversely, the preparation of basic salts of acidic portions that can be presented on an active agent is prepared in a similar manner using a pharmaceutically acceptable base such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, trimethylamine or Similar. The preparation of the esters involves the functionalization of the hydroxyl and / or carboxyl groups that may be present within the molecular structure of the drug. The esters are acyl-substituted derivatives typically of free alcohol groups, ie, portions derived from carboxylic acids of the formula RCOOH where R is alkyl and preferably is lower alkyl. The esters can be converted to free acids, if desired, by using conventional hydrogenolysis or hydrolysis procedures. The amides and prodrugs can also be prepared using techniques known to those skilled in the art or described in the relevant literature. For example, the amides can be prepared from esters, using suitable amine reagents, or they can be prepared from an anhydride or an acid chloride by reaction with ammonia or a lower alkylamine. Prodrugs are typically prepared by the covalent attachment of a portion, which result in a compound that is therapeutically inactive until it is modified by an individual's metabolic system. A set of formulations for gabapentin are those marketed by Pfizer Inc., under the trade name Neurontin®. Neurontin® Capsules, Neurontin® Tablets and the Neurontin Oral Solution "are supplied as either hard-coated printed capsules containing 100 mg, 300 mg and 400 mg gabapentin, elliptical film-coated tablets containing 600 mg and 800 mg of gabapentin or an oral solution containing 250 mg / 5 mL of gabapentin.The inactive ingredients for the capsules are lactose, corn starch and talcum.The capsule shell of 100 mg contains gelatin and titanium dioxide. 300 mg capsule shell contains gelatin, titanium dioxide and yellow iron dioxide.The 400 mg capsule shell contains gelatin, red iron oxide, titanium dioxide and yellow iron oxide.The inactive ingredients for the tablets are poloxamer 407, copolyividonum, corn starch, magnesium stearate, hydroxypropyl cellulose, talcum, candelilla wax and purified water.The inactive ingredients for the oral solution are n glycerin, xylitol, purified water and artificial cold strawberry anise flavor. In addition to these formulations, gabapentin and formulations are generally described in the following patents: US 6,683,112; US 6,645,528; US 6,627,211; US 6,569,463; US 6,544,998; US 6,531,509; 6,495,669; US 6,465,012; US 6,346,270; US 6,294,198; US 6,294,192; US 6,207,685; US 6,127,418; US 6,024,977; US 6,020,370; US 5,906,832; US 5,876,750; and US 4,960,931. A set of formulations for oxybutynin are those marketed by Ortho-McNeil Pharmaceuticals, Inc. under the trade name of Ditropan. The Ditropan® tablets are supplied containing 5 mg / tablets of the active ingredient, oxybutynin chloride and the inactive ingredients lactose anhydrous, microcrystalline cellulose, calcium stearate and blue lacquer # 1 FD &C. Ditropan® syrup is supplied as 5 mg / 5 mL of the active ingredient, oxybutynin chloride and the inactive ingredients citric acid, FD &C green # 3, flavor, glycerin, methyl paraben, sodium citrate, sorbitol, sucrose and water . Ditropan XL® is a long-acting tablet form of Ditropan® supplied containing either 5 mg of a pale yellow color) of oxybutynin chloride, 10 mg (pink) of oxybutynin chloride or 15 mg (gray color) of chloride of oxybutynin. The inactive ingredients are cellulose acetate, hydroxypropyl methylcellulose, lactose, magnesium stearate, polyethylene glycol, polyethylene oxide, synthetic iron oxides, titanium dioxide, polysorbate 80, sodium chloride and butylated hydroxytoluene. Oxybutynin is also supplied by Watson Pharmaceuticals under the trade name Oxytrol "(transdermal oxybutynin system) Oxytrol® is a transdermal patch designed to deliver oxybutynin continuously and consistently over an interval of 3 to 4 days.This is supplied as a patch of 39 cm2 containing 36 mg of oxybutynin, which is designed to deliver 3.9 mg / day.The patch is used continuously, and a new patch is applied every 3 to 4 days.A formulation useful in the present invention comprises a combination of gabapentin and chloride Oxybutynin The combination can be supplied in various pharmaceutical compositions in dosage forms as described herein A formulation for delivering the combination is in a tablet formulation Additional formulations for the combination of the present invention, such as capsules , syrups, etcetera (are also contemplated for the supply of the combination, and any description of tablet formulations is not proposed in any way to be limiting the possible modes of supply for the combination of the present invention. Tablets formulations useful for delivering the combination of gabapentin / oxybutynin useful in the present invention may comprise, in addition to the active ingredients in combination, functional excipients. Such excipients as are useful for the preparation of pharmaceutical compositions in a tablet formulation are known in the art and include known compounds that are useful as fillers, binders, lubricants, disintegrants, diluents, coatings, plasticizers, slip agents, compression aids. , stabilizers, sweeteners, solubilizers or other excipients that would be known to a person skilled in the pharmaceutical arts. The active ingredients of the combination useful in the present invention (gabapentin and oxybutynin) can be combined, particularly in tablet form, according to the ratios provided herein. The relative ratio of the active ingredients of the combination for use in the present invention is from about 1: 1 to about 1: 800, oxybutynin and gabapentin respectively, more preferably about 2.5: 200 to 2.5: 800, oxybutynin and gabapentin respectively . Generally, the ratio of oxybutynin to gabapentin in the combination is about 2.5: 50, about 2.5: 100, about 2.5: 150, about 2 2.55.50, about 2.5: 250, about 2 5 300, about 2.5: 350. , approximately 2. 5 400, approximately 2.5: 450, approximately 2. 5,500, approximately 2.5: 550, approximately 2. 5,600, approximately 2.5: 650, approximately 2. 5 700, approximately 2.5: 750 or approximately 2. 5 800 Alternatively, the ratio of oxybutynin to gabapentin in the combination is about 1.25: 50, about 1.25: 100, about 1.25: 150, about 1 1.2 255 200, about 1.25: 250, about 1. 25 300, approximately 1.25: 350, approximately 1. 25 400, approximately 1.25: 450, approximately 1. 25,500, approximately 1.25: 550, approximately 1.25 600, approximately 1.25: 650, approximately 1. 25: 700, approximately 1.25: 750 or approximately 1. 25: 800. Alternatively, the ratio of oxybutynin to gabapentin in the combination is about 5:50, about 5: 100, about 5: 150, about 5: 200, about 5: 250, about 5: 300, about 5: 350, about 5. : 400, about 5: 450, about 5: 500, about 5: 550, about 5: 600, about 5: 650, about 5: 700, about 5: 750 or about 5: 800. Examples of formulations for the preparation of tablets comprising gabapentin and oxybutynin in combination suitable for use in the present invention are given below in Tables 1 and 2.

The tablets according to the above formulations can be prepared according to a number of possible methods. A method used in the preparation of a tablet comprising a formulation as provided in the foregoing, includes the following steps: (1) sieving the ingredients through the 20 mesh screen, transferring to the granulator with impeller and shredder, and mixing for five minutes; (2) wet granulating the ingredients mixed with a binder solution (such as povidone or methocel); (3) transfer the wet granules to the fluid bed dryer and dry to% LOD values that are within a range of 1-2.5%; (4) grind the dry granules; (5) lubricate the ground granules (such as with magnesium stearate) in the mixer; (6) compress into tablets. Other derivatives and analogs of the active agents can be prepared using standard techniques known to those skilled in the synthetic organic chemistry art or can be deduced by reference to the relevant literature. In addition, the chiral active agents may be in isomerically pure form, or they may be administered as a racemic mixture of isomers. Pharmaceutical Compositions and Dosage Forms Suitable compositions and dosage forms include tablets, capsules, caplets, pills, gel capsules, troches, dispersions, suspensions, solutions, syrups, transdermal patches, gels, powders, magmas, lozenges, creams, pastes , plasters, lotions, discs, suppositories, liquid sprays for nasal and oral administration, dry powder or aerosolized formulations for inhalation or the like. In addition, those of ordinary skill in the art can readily deduce suitable formulations involving these compositions and dosage forms, including those formulations as described elsewhere herein. Oral Dosage Forms Oral dosage forms include tablets, capsules, caplets, solutions, suspensions and / or syrups, and may also comprise a plurality of granules, beads, powders or pellets that may or may not be encapsulated. Such dosage forms are prepared using conventional methods known to those in the field of pharmaceutical formulation and described in the relevant texts, for example, in Remington: The Science and Practice of Pharmacy, supra). Tablets and capsules represent the most convenient oral dosage forms, in which case solid pharmaceutical carriers are employed. The tablets can be manufactured using standard tablet processing methods and equipment. One method of forming tablets is by direct compression of a powdery, crystalline or granular composition containing the active agent (s), alone or in combination with one or more carriers, additives or the like. As an alternative to direct compression, tablets can be prepared using wet granulation or dry granulation processes. The tablets can also be molded rather than compressed, starting with a moist or otherwise treatable material; however, compression and granulation techniques are preferred. In addition to the active agent (s), then, tablets prepared for oral administration using the method of the invention will generally contain other materials such as binders, diluents, lubricants, disintegrants, fillers, stabilizers, surfactants, preservatives. , coloring agents, flavoring agents and the like. The binders are used to impart cohesive qualities to a tablet, and in this way ensure that the tablet remains intact after compression. Suitable binder materials include, but are not limited to, starch (including corn starch and pregelatinized starch), gelatin, sugars (including sucrose, glucose, dextrose and lactose), polyethylene glycol, propylene glycol, natural and synthetic waxes and gums, for example, acacia sodium alginate, polyvinylpyrrolidone, cellulosic polymers (including hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose and the like) and Veegum. Diluents are typically necessary to increase the volume so that a practical size tablet is finally provided, suitable diluents include dicalcium phosphate, calcium sulfate, lactose, cellulose, kaolin, mannitol, sodium chloride, dry starch and sugar in dust. Lubricants are used to facilitate the manufacture of tablets; Examples of suitable lubricants include, for example, vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and theobroma oil, glycerin, magnesium stearate, calcium stearate and acid. Stearic The stearates, if present, preferably represent no more than about 2% by weight of the core containing the drug. The disintegrants are used to facilitate the disintegration of the tablet, and are generally starches, clays, celluloses, algins, gums or cross-linked polymers. Fillers include, for example, materials such as silicon dioxide, titanium dioxide, alumina, talc, kaolin, powdered cellulose and microcrystalline cellulose, as well as soluble materials such as mannitol, urea, sucrose, lactose, dextrose, sodium chloride and sorbitol. The stabilizers are used to inhibit or retard the decomposition reactions of the drug and include, by way of example, oxidative reactions. The surfactants may be anionic, cationic, amphoteric or nonionic surfactants. The dosage form can also be a capsule, in which case the composition containing the active compound can be encapsulated in the form of a solid liquid (including particulate materials such as granules, beads, powders or pellets). either hard or soft, and are generally made of gelatin, starch or a cellulosic material, with the preferred gelatin capsules.The two-piece hard gelatin capsules are preferably sealed, such as with gelatin bands or the like. , for example, Remington: The Science and Practice of Pharmacy, cited supra), which describes materials and methods for preparing encapsulated pharmaceutical substances. If the composition containing the active agent is present within the capsule in liquid form, a liquid carrier is necessary to dissolve the active agent (s). The carrier must be compatible with the capsule material and all components of the pharmaceutical composition, and must be suitable for ingestion. The solid dosage forms, whether tablets, capsules, caplets or particulate materials, if desired, can be coated to provide a delayed release. Dosage forms with delayed release coatings can be manufactured using standard coating methods and equipment. Such procedures are known to those skilled in the art and described in the relevant texts (for example, in Remington: The Science and Practice of Pharmacy, supra). Generally, after the preparation of the solid dosage form, a delayed release coating composition is applied using a coating tray, an airless spray technique, fluidized bed coating equipment, or the like. The delayed release coating compositions comprise a polymeric material, for example, cellulose butyrate phthalate, cellulose hydrogen phthalate, cellulose propionate phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, phthalate hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate, dioxypropyl methylcellulose succinate, carboxymethyl ethylcellulose, hydroxypropyl methylcellulose acetate succinate, polymers and copolymers formed of acrylic acid, methacrylic acid and esters thereof. The sustained release dosage forms provide for the release of the drug over a long period of time, and may or may not be delayed release. Generally, as will be appreciated by those of ordinary skill in the art, sustained release dosage forms are formulated by dispersing a drug within a matrix of a gradually bioerodible (hydrolysable) material such as an insoluble plastic, a hydrophilic polymer, a compound fat, or by coating a dosage form containing solid drug with such a material. Insoluble plastic matrices may be comprised of, for example, polyvinyl chloride or polyethylene. Useful hydrophilic polymers to provide a sustained release coating or cellulose matrix polymers include, without limitation: cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropylmethyl cellulose phthalate, hydroxypropyl cellulose phthalate, hexahydrophthalate of cellulose, cellulose acetate hexahydrophthalate and sodium carboxymethylcellulose; polymers and copolymers of acrylic acid, preferably formed from acrylic acid, methacrylic acid, alkyl esters of alkyl acid, alkyl esters of methacrylic acid and the like, for example copolymers of acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and / or ethyl methacrylate, with a terpolymer of ethyl acrylate, methyl methacrylate and trimethylammonioethyl methacrylate chloride (sold under the tradename Eudragit RS) preferred; vinyl polymers and copolymers, such as polyvinyl pyrrolidone, polyvinyl acetate, polyvinylacetate phthalate, copolymer of. crotonic acid vinyl acetate and ethylene vinyl acetate copolymer; zeina; and lacquer, ammonia lacquer, acetyl alcohol lacquer and n-butyl lacquer stearate. Fatty compounds for use as a sustained release matrix material include, but are not limited to, waxes, generally (eg, carnauba wax) and glyceryl tristearate. Transmucosal Compositions and Dosage Forms Although the present compositions can be administered orally, other methods of administration are also suitable. For example, transmucosal administration can be advantageously employed. Transmucosal administration is carried out using any type of formulation or dosage unit suitable for application to mucosal tissue. For example, the selected active agent can be administered to the buccal mucosa in a sticky tablet or patch, sublingually administered by placing a solid dosage form under the tongue, lingually administered by placing a solid dosage form on the tongue, administering a salt as droplets or a nasal spray, administered by inhalation of an aerosol formulation, a non-aerosol liquid formulation, a dry powder, placed in or near the rectum ("transrectal" formulations), or administered to the urethra as a suppository, ointment or similar. Preferred buccal dosage forms will typically comprise a therapeutically effective amount of the selected active agent and a bioerodible (hydrolyzable) polymer carrier which may also serve to adhere the dosage form to the buccal mucosa. The buccal dosage unit is manufactured to erode over a predetermined period of time, wherein drug delivery is essentially provided throughout. The period of time is typically in the range of about 1 hour to about 72 hours. The preferred oral drug supply is preferably presented for a period of time from about 2 hours to about 24 hours. The oral drug supply for short-term use preferably should occur for a period of time from about 2 hours to about 8 hours, more preferably over a period of time from about 3 hours to about 4 hours. The oral drug delivery as necessary will preferably occur for a period of time from about 1 hour to about 12 hours, more preferably from about 2 hours to about 8 hours, much more preferably from about 3 hours to about 6 hours. The sustained oral drug delivery will preferably occur over a period of time from about 6 hours to about 72 hours, more preferably from about 12 hours to about 48 hours, much more preferably from about 24 hours to about 48 hours. oral drug delivery, as will be appreciated by those skilled in the art, avoids the disadvantages encountered with the administration of oral drug, for example slow absorption, degradation of the active agent by fluids present in the gastrointestinal tract and / or inactivation of the first step in the liver The "therapeutically effective amount" of the active agent in the oral dosage unit will of course depend on the potency of the agent and the proposed dosage, which, in turn, is dependent on the implicit treatment of the particular individual, the specific indication and the like. The oral dosage unit will generally contain from about 1.0% by weight to about 60% by weight of active agent, preferably in the order of about 1% by weight to about 30% by weight of active agent. With respect to the bioerodible (hydrolyzable) polymeric carrier, it will be appreciated that virtually any carrier of that class can be used, as long as the desired drug release profile is not compromised, and the carrier is compatible with the calcium channel modulator a2d subunit which is administered and any of the other components of the buccal dosage unit. Generally, the polymeric carrier comprises a hydrophilic polymer (water soluble and water swellable) that adheres to the moist surface of the buccal mucosa. Examples of polymeric carriers useful herein include an acrylic acid polymer and, for example, those known as "carbomer" (Carbopol®, which can be obtained from B. F. Goodrich, is one such polymer). Other suitable polymers include, but are not limited to: hydrolyzed polyvinyl alcohol; polyethylene oxides (for example, Sentry Polyox water-soluble resins), available from Union Carbide, polyacrylates (for example, Ganterez®, obtainable from GAF), polymers and vinyl copolymer, polyvinylpyrrolidone, dextran, guar gum pectins; starches; and cellulosic polymers such as hydroxypropyl methylcellulose, (eg, Methocel®, which can be obtained from Dow Chemical Company), hydroxypropyl cellulose (eg, Klucel®, which can be obtained from Dow), ethers of hydroxypropyl cellulose (see, for example, U.S. Patent No. 4,704,285 to Alderman), hydroxyethyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, ethyl cellulose, cellulose acetate phthalate, cellulose acetate butyrate, and the like. components can also be incorporated into the buccal dosage forms described herein.Additional components include, but are not limited to, disintegrants, dilutes, and entities, binders, lubricants, flavorings, colorants, preservatives and the like. Examples of disintegrants that can be used include, but are not limited to, crosslinked polyvinylpyrrolidones, such as crospovidone (e.g., Polyplasdone "XL, which can be obtained from GAF), crosslinked carboxyl methylcelluloses, such as croscarmellose (e.g. di-sol®, which can be obtained from FMC), alginic acid and sodium carboxymethyl starches (for example, Explotabt®, which can be obtained from Edward Medell Co., Inc.), methylcellulose, agar bentonite and alginic acid Suitable diluents are those which are generally useful in pharmaceutical formulations prepared using compression techniques, for example, dicalcium phosphate dihydrate (for example, Di-Tab®, which can be obtained from Stauffer), sugars that have been processed by co-crystallization with dextrin (e.g., co-crystallized sucrose and dextrin such as Di-Pak, which can be obtained from Amstar), calcium phosphate, cellulose, kaolin, peanut tol, sodium chloride, dry starch, powdered sugar and the like. Binders, if used, are those that increase adhesion. Examples of such binders include, but are not limited to, starch, gelatin and sugars such as sucrose, dextrose, melases and lactose. Particularly preferred lubricants are stearates and stearic acid and an optimum lubricant is magnesium stearate. The sublingual and lingual dosage forms include tablets, creams, ointments, lozenges, pastes and any other solid dosage form where the active ingredient is mixed in a disintegrable matrix.

The tablet, cream, ointment or paste for sublingual or lingual delivery comprises a therapeutically effective amount of the selected active agent and one or more conventional non-toxic carriers suitable for administration of the sublingual or lingual drug. The sublingual and lingual dosage forms of the present invention can be manufactured using conventional processes. The sublingual and lingual dosing units are manufactured to rapidly disintegrate. The period of time for complete disintegration of the dosage unit is typically in the range of from about 10 seconds to about 30 minutes, and optimally is less than 5 minutes. Other components may also be incorporated in the sublingual and lingual dosage forms described herein. Additional components include, but are not limited to, binders, disintegrants, wetting agents, lubricants, and the like. Examples of binders that can be used include water, ethanol, polyvinylpyrrolidone; starch solution, gelatin solution and the like. Suitable disintegrants include dry starch, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic monoglyceride, lactose and the like. Wetting agents, if used, include glycerin, starches and the like. Particularly preferred lubricants are stearates and polyethylene glycol. Additional components that can be incorporated into the sublingual and lingual dosage forms are known or will be apparent to those skilled in the art (See, for example, Remington: The Science and Practice of Pharmacy, supra). For transurethral administration, the formulation comprises a urethral dosage form containing the active agent and one or more selected carriers or excipients, such as water, silicone, waxes, gelatinous petroleum substance, polyethylene glycol ("PEG"), propylene glycol (" PG "), liposomes, sugars such as mannitol and lactose, and / or a variety of other materials, with polyethylene glycol and particularly preferred derivatives thereof. Depending on the particular active agent administered, it may be desirable to incorporate a transurethral permeation enhancer in the urethral dosage form. Examples of suitable transurethral permeation enhancers include dimethyl sulfoxide ("DMSO"), dimethylformamide ("DMF"), N, N-dimethylacetamide ("DMA"), decylmethylsulfoxide ("Cío MSO"), polyethylene glycol monolaurate ("PEGML"), glycerol monolaurate, lecithin, 1-substituted azacycloheptan-2-ones, particularly l-n-dodecylcyclazacycloheptan-2-one (available under the trademark Azonet® by Nelson Research & Development Co., Irvine, California), SEPA® (available from Macrochem Co., Lexington, Mass.), surfactants as discussed above, including, for example, Tergitol®, Nonoxynol-9® and TWEEN-80® - and lower alkanols such as ethanol. The administration of transurethral drug, as explained in U.S. Patent Nos. 5,242,391, 5,474,535, 5,686,093 and 5,773,020, can be carried out in a number of different ways using a variety of urethral dosage forms. For example, the drug can be introduced into the urethra from a flexible tube, compressible bottle, pump or aerosol spray. The drug can also be contained in coatings, pellets or suppositories that are absorbed, fused or bioerodized in the urethra. In certain embodiments the drug is included in a coating on the outer surface of a penile insert. It is preferred, although not essential, that the drug be delivered from at least about 3 cm in the urethra, and preferably from at least about 7 cm in the urethra. Generally, the delivery is at least about 3 cm to about 8 cm in the urethra will provide effective results in conjunction with the present method.

Urethral suppository formulations containing PEG or a PEG derivative can be conveniently formulated using conventional techniques, for example, compression molding, thermal molding or the like, as will be appreciated by those skilled in the art and as described in the pertinent literature in pharmaceutical texts. (See, for example, Remington: The Science and Practice of Pharmacy, supra), which discloses typical methods for preparing pharmaceutical compositions in the form of urethral suppositories. The PEG or PEG derivative preferably has a molecular weight in the range of about 200 to about 2,500 g / mol, more preferably in the range of about 1,000 to about 2,000 g / mol. Suitable polyethylene glycol derivatives include polyethylene glycol fatty acid esters, for example, polyethylene glycol monostearate, polyethylene glycol sorbitan esters, for example, polysorbates and the like. "Depending on the particular active agent, it may also be preferred that urethral suppositories contain one or more effective solubilizing agents to increase the solubility in the PEG or other transurethral vehicle It may be desirable to deliver the active agent in a urethral dosage form that provides for controlled or sustained release of the agent In such a case, the dosage form comprises a biocompatible, biodegradable material, typically a biodegradable polymer Examples of such polymers include polyesters, polyalkylcyanoacrylates, polyorthoesters, polyanhydrides, albumin, gelatin and starch, as explained, for example, in PCT publication No. WO 96/40054, these and other polymers can be to provide biodegradable microparticles that allow controlled and sustained drug release, in turn minimizing the frequency of administration required. The urethral dosage form will preferably comprise a suppository which is in the order of about 2 to about 20 mm in length, preferably about 5 to about 10 mm in length and less than about 5 mm in width, preferably less than about 2 mm wide. The weight of the suppository will typically be in the range of about 1 mg to about 100 mg, preferably in the range of about 1 mg to about 50 mg. However, it will be appreciated by those skilled in the art that the size of the suppository may vary, depending on the potential of the drug, the nature of the formulation and other factors. The transurethral drug delivery may involve an "active" delivery mechanism such as iontophoresis, electroporation or phonophoresis. Devices and methods for drug delivery in this manner are well known in the art. The iontophoretically assisted drug delivery is, for example, described in PCT publication No. WO 96/40054, cited above. Briefly, the active agent is induced through the urethral wall by means of an electrical current passed from an external electrode to a second electrode contained within or attached to a urethral catheter. Preferred transrectal dosage forms include rectal suppositories, creams, ointments and liquid formulations (enemas). The suppository, cream, ointment or liquid formulation for transrectal delivery comprises a therapeutically effective amount of the selected phosphodiesterase inhibitor and one or more conventional non-toxic carriers for the administration of transrectal drug. The transrectal dosage forms of the present invention can be manufactured using conventional processes. The transrectal dosage unit can be manufactured to disintegrate rapidly or over a period of several hours. The period of time for complete disintegration preferably is in the range of about 10 minutes to about 6 hours, and optimally is less than about 3 hours.

Other components may also be incorporated in the transrectal dosage form described herein. Additional components include, but are not limited to, hardening agents, antioxidants, preservatives and the like. Examples of curing agents that can be used include, for example, paraffin, white wax and yellow wax. Preferred antioxidants, if used, include sodium bisulfite and sodium metabisulfite. Preferred vaginal or perivaginal dosage forms include vaginal suppositories, creams, ointments, liquid formulations, pessaries, tampons, gels, pastes, foams or sprays. The suppository, cream, ointment, liquid formulation, pessary, tampon, gel, paste, foam or spray for vaginal or perivaginal delivery comprises a therapeutically effective amount of the selected active agent and one or more conventional non-toxic carriers suitable for drug delivery vaginal or perivaginal. The vaginal or perivaginal forms of the present invention can be manufactured using conventional processes as described in Remington: The Science and Practice of Pharmacy, supra (see also formulations of drugs as adapted in U.S. Patent Nos. 6,515,198; 6,500,822; 6,417,186; 6,416,779, 6,376,500, 6,355,641, 6,258,819, 6,172,062, and 6,086,909). The vaginal or perivaginal dosing unit can be manufactured to disintegrate rapidly over a period of time of several hours. The period of time for complete disintegration preferably is in the range of about 10 minutes to about 6 hours, and optimally is less than about 3 hours. Other components may also be incorporated in the vaginal or perivaginal dosage forms described herein. Additional components include, but are not limited to, hardening agents, antioxidants, preservatives and the like. Examples of curing agents that can be used include, for example, paraffin, white wax and yellow wax. Preferred antioxidants, if used, include sodium bisulfite and sodium metabisulfite. The active agents can also be administered intranasally or by inhalation. The compositions for intranasal administration are generally liquid formulations for administration as a spray in the form of drops, although powder formulations for intranasal administration are also known, for example, insufflations, such as gels, creams, pastes or nasal ointments. . For liquid formulations, the active agent can be formulated in a solution, for example water or isotonic saline, regulated or unregulated at the pH, or as a suspension. Preferably such solutions or suspensions are isotonic with respect to nasal secretions and of about the same pH, ranging from, for example, from about pH 4.0 to about pH 7.4 or, from about pH 6.0 to about pH 7.0. Regulatory solutions must be physiologically compatible and include, simply by way of example, phosphate buffer solutions. In addition, various devices are available in the art for the generation of droplets, droplets and sprays, including drippers, compressible bottles and manually and electrically operated intranasal pump jets. Intranasal carriers containing the active agent can also include gels, creams, pastes or nasal ointments with a viscosity of, for example, about 10 to about 6500 cps, or larger, depending on the desired sustained contact with the nasal mucosal surfaces. Such carrier viscous formulations can be based, simply by way of example, alkylcelluloses and / or other biocompatible carriers of high viscosity, well known in the art (see, for example, Remington: The Science and Practice of Pharmacy, supra). Other ingredients, such as preservatives known in the art, dyes, lubricants or viscous mineral or vegetable oils, perfumes, natural or synthetic extracts of plants such as aromatic oils, and humectants and viscosity enhancers such as, for example, glycerol, also they can be included to provide additional viscosity, moisture retention and a pleasant texture and odor for the formulation. Formulations for inhalation can be prepared as an aerosol, either an aerosol in solution in which the active agent is solubilized in a carrier (eg, propellant) or an aerosol in dispersion in which the active agent is suspended or dispersed for all a carrier and an optional solvent. Non-aerosol formulations for inhalation may take the form of a liquid, typically an aqueous suspension, although aqueous solutions may also be used as well. In such a case, the carrier is typically a sodium chloride solution having a concentration such that the formulation is isotonic relative to normal body fluid. In addition to the carrier, the liquid formulations may contain water and / or excipients including an antimicrobial preservative (e.g., benzalkonium chloride, benzethonium chloride, chlorobutanol, phenylethyl alcohol, thimerosal, and combinations thereof), a regulatory agent (e.g. , citric acid, potassium metaphosphate, potassium phosphate, sodium acetate, sodium citrate and combinations thereof), a surfactant (eg, polysorbate 80, sodium lauryl sulfate, sorbitan monopalmitate and combinations thereof), and / or a suspending agent (eg, agar, bentonite, microcrystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, tragacanth, veegum and combinations thereof). Non-aerosol formulations for inhalation may also comprise dry powder formulations, particularly insufflations in which the powder has an average particle size of from about 0.1 μm to about 50 μm, preferably from about 1 μm to about 25 μm. Topical Formulations Topical formulations may be in any form suitable for application to the body surface, and may comprise, for example, an ointment, cream, gel, lotion, solution, paste or the like, and / or may be prepared to contain liposomes, micelles and / or microspheres. The preferred topical formulations herein are ointments, creams and gels. Ointments, as is well known in the pharmaceutical formulating art, are semi-solid preparations that are typically based on petrolatum or other petroleum derivatives. The specific ointment base to be used, as will be appreciated by those skilled in the art, is one that will provide the optimal drug delivery and, preferably, provide other desired characteristics as well, for example, emolliency or the like. As with other carriers or vehicles, a base or ointment should be inert, stable, non-irritating and non-sensitizing. As it is explained, in Remington: The Science and Practice of Pharmacy, supra, ointment bases can be grouped into four classes: oleaginous bases; emulsifiable bases; emulsion base; and water-soluble base. Oleaginous ointment bases include, for example, vegetable oils, fats obtained from animals and semi-solid hydrocarbons obtained from petroleum. Emulsifiable ointment bases, also known as absorbent ointment bases, contain little or no water and include, for example, hydroxystearin sulfate, anhydrous lanolin and hydrophilic petrolatum. The emulsion ointment bases are either water-in-oil (W / O) emulsions or oil-in-water (O / W) emulsions, and include, for example, cetyl alcohol, glyceryl monostearate, lanolin and stearic acid. Preferred water-soluble ointment bases are prepared from polyethylene glycols of variable molecular weight (See, for example, Remington: The Science and Practice of Pharmacy, supra). The creams, as is also well known in the art, are viscous liquids or semi-solid emulsions, either oil-in-water or water-in-oil. The cream bases are washable with water, and contain an oily phase, an emulsifier and an aqueous phase. The oily phase, also called the "internal" phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl and stearyl alcohol. The aqueous phase usually, although not necessarily, exceeds the oily phase by volume, and generally contains a humectant. The emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant. As will be appreciated by those working in the field of pharmaceutical formulation, gels are suspension, semi-solid type systems. The single phase gels contain organic macromolecules distributed substantially uniformly throughout the carrier liquid, which is typically aqueous, but also, preferably, contains an alcohol and, optionally, an oil. Preferred "organic macromolecules", ie, gelling agents, are polymers of crosslinked acrylic acid such as the "carbomer" family of polymers, for example, carboxypolyalkylenes which can be obtained commercially under the trademark CarbopolX®. Also preferred are hydrophilic polymers such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers and polyvinyl alcohol; cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate and methylcellulose; gums such as tragacanth and xanthan gums; sodium alginate; and gelatin. In order to prepare a uniform gel, dispersing agents such as alcohol or glycerin can be added, the gelling agent can be dispersed by grinding, mechanically mixing and / or stirring. Various additives, known to those skilled in the art, can be included in topical formulations. For example, the solubilizers can be used to solubilize certain active agents. For those drugs that have an unusually low rate of permeation through the skin or mucosal tissue, it may be desirable to include a permeation enhancer in the formulation, suitable enhancers are as described elsewhere herein. Transdermal Administration The compounds of the invention can also be administered through the skin or mucosal tissue using conventional transdermal drug supplies, wherein the agent is contained within a laminated structure (typically referred to as a transdermal "patch") that It serves as a drug delivery device to be fixed to the skin. The transdermal drug delivery may involve passive diffusion or may be facilitated using electrotransport, for example iontophoresis. In a typical transdermal "patch", the drug composition is comprised in a layer or "deposits" implicit in a top backing layer. The laminated structure can contain a single deposit, or it may contain multiple deposits. In a type of patch, referred to as a "monolithic" system, the reservoir is comprised of a polymeric matrix of a pharmaceutically acceptable contact adhesive material that serves to secure the system to the skin during drug delivery. Examples of suitable skin contact adhesive materials include, but are not limited to, polyethylenes, polysiloxanes, polyisobutylenes, polyacrylates, polyurethanes, and the like. Alternatively, the reservoir containing the drug and the contact adhesive to the skin are separated and in separate layers, with the adhesive involving the deposit which, in this case, can be a polymeric matrix as described above, or can be a liquid or hydrogel deposit or it can take some other form. The backing layer in these laminates, which serves as the upper surface of the device, functions as the primary structural element of the laminated structure and provides the device with most of its flexibility. The material selected for the backing material can be selected so that it is substantially impermeable to the active agent and any of the other materials that are present, the backing preferably being made of a sheet or film of a flexible elastomeric material. Examples of polymers that are suitable for the backing layer include polyethylene, polypropylene, polyesters, and the like. During storage - and before use, the laminated structure includes a release liner. Immediately before use, this layer is removed from the device to expose the basal surface thereof, either the drug reservoir or a separate contact adhesive layer, so that the system can be fixed to the skin. The release liner must be made of a material impermeable to the drug / vehicle. Transdermal drug delivery systems may also contain a skin permeation enhancer. That is, because the inherent impermeability of the skin to some drugs may be too low to allow therapeutic levels of the drug to pass through a reasonably sized area of non-broken skin, it is necessary to co-administer a skin permeation enhancer. with such drugs. Suitable enhancers are well known in the art and include, for example, those enhancers listed in the above in transmucosal compositions. Parenteral Administration Parenteral administration, if used, is generally characterized by injection, including intramuscular, intraperitoneal, intravenous (IV) and subcutaneous injection. Injectable formulations can be prepared in conventional ways, either as liquid solutions or suspensions; solid forms suitable for solution or suspension in liquid before injection, or as emulsions. Preferably, sterile injectable suspensions are formulated according to techniques known in the art using suitable wetting dispersing agents and suspending agents. The sterile injectable formulation can also be a sterile injectable solution or a suspension in a non-toxic parenterally acceptable diluent or solvent. Among the vehicles and acceptable solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, fixed, sterile oils are conventionally employed as a solvent or suspension medium. A more recently revised method for parenteral administration involves the use of a slow release or sustained release system (See, for example, U.S. Patent No. 3,710,795). Intravesical Administration Intravesical administration, if used, is generally characterized by administration directly into the bladder and may include methods as described elsewhere herein. Other methods of intravesical administration may include those described in U.S. Patent Nos. 6,207,180 and 6,039,967, as well as other methods that are known to one skilled in the art. Intrathecal Administration Intrathecal administration, if used, is generally characterized by administration directly into the intrathecal space (where fluid flows around the spinal cord). A common system used for intrathecal administration is the intrathecal APT treatment system available from Medtronic, Inc. APT Intratecal uses a small pump that is surgically placed under the skin of the abdomen to deliver the medication directly into the intrathecal space. The medication is delivered through a small tube called a catheter that is also surgically placed. The medication can then be administered directly to the cells in the spinal cord involved in transporting the sensory and motor signals associated with disorders of the lower urinary tract. Another system available from Medtronic that is commonly used for intrathecal administration is the SynchroMed Infusion System programmable, fully implantable. The SynchroMed® Infusion System has two parts that are both placed on the body during a surgical procedure: the catheter and the pump. The catheter is a small soft tube. One end is connected to the catheter orifice of the pump and the other end is placed in the intrathecal space. The pump is a round metal device approximately 2.5 cm (1 inch) thick, 8.5 cm (three inches) in diameter, and weighs approximately 205 g (approximately six ounces) that stores and releases prescribed amounts of medication directly into the intrathecal space. This is made of titanium, a medical-grade, lightweight metal. The reservoir is the space inside the pump that holds the medication. The filler hole is a raised central portion of the pump through which the pump is filled. The doctor or nurse inserts a needle through the patient's skin and through the filling hole to refill the pump. Some pumps have a side catheter access hole that allows the doctor to inject other medications or sterile solutions directly into the catheter, bypassing the pump. The SynchroMed® pump automatically delivers a controlled amount of medication through the catheter to the intrathecal space around the spinal cord, where it is most effective. The exact dosage, proportion and timing prescribed by the doctor are entered into the pump using a programmer, a device similar to an external computer that controls the pump memory. The information about the prescription of the patient is stored in the pump memory. The doctor can easily review this information when using the programmer. The programmer communicates with the pump by radio signals that allow the doctor to tell how the pump is operating at any given time. The doctor can also use the programmer to change your medication dosage. Intrathecal administration methods may include those described in the foregoing, available from Medtronic, as well as other methods that are known to one skilled in the art. Additional Dosage Formulations and Drug Delivery Systems As compared to traditional drug delivery procedures, some controlled-release technologies rely on the modification of both macromolecules and synthetic small molecules to allow them to be actively instead of passively absorbed. in the body. For example, XenoPort Inc. uses technology that takes existing molecules and re-designs them to create new chemical entities (single molecules) that have improved pharmacological properties to either: 1) lengthen the short half-life of a drug; 2) overcome poor absorption; and / or 3) deal with the distribution of deficient drug to the target tissues. Techniques for extending the short half-life of a drug include the use of prodrugs with proportions of slow segmentation to release the drugs over time or that are coupled to transporters in the small and large intestines to allow the use of delivery systems. oral sustained supply, as well as drugs that favor active transport systems. Examples of such controlled release formulations, tablets, dosage forms and drug delivery systems and which are suitable for use with the present invention are described in the following applications of US patents and published PCTs assigned to Xenoport Inc .: US 20030158254; US 20030158089; US 20030017964; US 2003130246; WO 02100172; WO 02100392; WO 02100347; WO 02100344; WO 0242414; WO 0228881; WO 0228882; WO 0244324; WO 0232376; WO 0228883; and WO 0228411. In particular, XP13512 from Xenoport is a Gabapentin Transported Prodrug that has been designed to utilize high capacity transport mechanisms located in both the small and large intestine and to rapidly convert gabapentin once into the body. In contrast to gabapentin itself, XP13512 was shown in preclinical and clinical studies that produces blood levels proportional to the dose of gabapentin through a wide range of oral doses, and that is efficiently absorbed from the small intestine. Some other controlled-release technologies rely on methods that promote or increase gastric retention, such as those developed by Depomed Inc. Because many drugs are better adsorbed in the stomach and upper portions of the small intestine, Depomed has developed tablets that swell in the stomach during the tabletop or feeding mode so that They treat similar to undigested food. These tablets therefore settle securely and neutrally in the stomach for 6, 8 or more hours and deliver the drug at a desired rate and time to the upper gastrointestinal sites. Specific technologies in this area include: 1) tablets that slowly erode in gastric fluids to deliver drugs at almost a constant rate (particularly useful for highly insoluble drugs); 2) bi-layer tablets that combine drugs with different characteristics in a single tablet (such as a highly insoluble drug in an erosion layer and a soluble drug in a diffusion layer for the sustained release of both); 3) combination tablets that can either deliver drugs simultaneously or in sequence for a desired period of time (including an initial release of a fast-acting drug followed by the slow and sustained delivery of another drug) Examples of such controlled release formulations which are suitable for use with the present invention and which depend on gastric retension during tabletop or feeding mode, include tablets, dosage forms and drug delivery systems in the following US patents assigned to Depomed Inc .: US 6,488,962, US 6,451,808, US 6,340,475, US 5,972,389, US 5,582,837, and US 5,007,790, Examples of such controlled release formulations which are suitable for use with the present invention and which depend on gastric retention during tabletop or feeding mode. , include tablets, dosage forms and drug delivery system in the US patent and published PCT applications assigned to Depomed Inc.: US 20030147952; US 20030104062; US 20030104053; US 20030104052; US 20030091630; US 20030044466; US 20030039688; US 20020051820; WO 0335040; WO 0335039; WO 0156544; WO 0132217; WO 9855107; WO 9747285; and WO 9318755. Other controlled release systems include those developed by ALZA Corporation based on: 1) osmotic technology for oral delivery; 2) transdermal delivery via patches; 3) the liposomal supply via the intravenous injection; 4) osmotic technology for long-term delivery via implants; and 5) deposit technology designed to supply agents for periods of days to a month. ALZA's oral delivery systems include those that employ osmosis to provide controlled, precise drug delivery for up to 24 hours for both poorly soluble and highly soluble drugs, as well as those that deliver high-dose drugs that meet the requirements of high drug load The ALZA controlled transdermal delivery systems provide drug delivery through the intact skin for a period of one week with a single application to improve drug absorption and deliver constant amounts of the drug into the bloodstream over time. The liposomal delivery systems of ALZA involve lipid nanoparticles that speed up recognition by the immune system due to its unique polyethylene glycol (PEG) coating, allowing precise delivery of drugs to specific areas of the body's disease. ALZA has also developed osmotically induced systems to allow the continuous supply of small drugs, peptides, proteins, DNA and other bioactive macromolecules for up to one year for systemic or tissue-specific therapy. Finally, the ALZA deposit injection therapy is designed to deliver biopharmaceutical agents and small molecules over a period of days to a month using a nonaqueous polymer solution for the stabilization of macromolecules and a unique delivery profile. Examples of controlled release formulations, tablets, dosage forms, and drug delivery systems that are suitable for "use with the present invention are described in the following U.S. patents assigned to ALZA Corporation: US 4,367,741; 4,402,695; US 4,418,038; US 4,434,153; US 4,439,199; US 4,450,198; US 4,455,142; US 4,455,144; US 4,484,923; US 4,486,193; US 4,489,197; US 4,511,353; US 4,519,801; US 4,526,578; US 4,526,933; US 4,534,757; US 4,553,973; US 4,559,222; US 4,564,364; US 4,578,075; US 4,588,580; US 4, 610, 686 US 4, 618,487; US 4,627,851 US 4,629,449 US 4,642,233 US 4,649,043; US 4,650,484 US 4,659,558 US 4,661,105 US 4,662,880; US 4,675,174 US 4,681,583 US 4,684,524 US 4,692,336; US 4,693,895 US 4,704,119 US 4,705,515 US 4,717,566; US 4,721,613 US 4,723,957 US 4,725,272 US 4,728,498; US 4,743,248 US 4,747,847 US 4,751,071 US 4,753,802; US 4,755,180 US 4,756,314 US 4,764,380 US 4,773,907; US 4,777,049 US 4,781,924 US 4,786,503 US 4,788,062; US 4,810,502 US 4,812,313 US 4,816,258 US 4,824,675; US 4,834, -979 US 4,837,027 US 4,842,867 US 4,846,826; US 4,847,093 US 4,849,226 US 4,851,229 US 4,851,231; US 4,851,232 US 4,853,229 US 4,857,330; US 4,859,470; US 4,863,456; US 4,863,744; US 4,865,598, US 4,867,969, US 4,871,548, US 4,872,873; US 4,874,388, US 4,876,093, US 4,892,778, US 4,902,514; US 4,904,474, US 4,913,903, US 4,915,949, US 4,915,952; US 4,917,895, US 4,931,285, US 4,946,685; US 4,948,592; US 4,954,344, US 4,957,494, US 4,960,416, US 4,961,931; US 4,961,932, US 4,963,141, US 4,966,769, US 4,971,790; US 4,976,966; US 4,986,987, US 5,006,346; US 5,017,381; US ,019,397; US 5,023,076, US 5,023, -088; US 5,024,842; US ,028,434; US 5,030,454, US 5,071,656; US 5,077,054; US ,082, 668, US 5,104,390, US 5,110,597, US 5,122,128; US ,125,894, US 5,141,750, US 5,141,752, US 5,156,850; US ,160,743, US 5,160,744, US 5,169,382, US 5,171,576; US ,176,665, US 5,185,158, US 5,190,765, US 5,198,223; US ,198,229, US 5,200,195, US 5,200,196, US 5,204,116; US ,208,037, US 5,209,746, US 5,221,254, US 5,221,278; US ,229,133, US 5,232,438, US 5,232,705, US 5,236,689; US ,236,714, US 5,240,713, US 5,246 / 710, US 5,246,711; US ,252,338, US 5,254,349, US 5,266,332, US 5,273,752; US ,284,660, US 5,286,491, US 5,308,348, US 5,318,558; US ,320,850, US 5,322,502, • US 5,326,571, US 5,330,762; US ,338,550, • US 5,340,590, • US 5,342,623, • US 5,344,656; US ,348,746, • US 5,358,721, • US 5,364,630, US 5,376,377; US ,391,381, US 5,402,777, • US 5,403,275, US 5,411,740; US ,417, 675, US 5,417, 676, • US 5,417,682, • US 5,423,739; US ,424,289, US 5,431,919, • US 5,443,442, US 5,443,459; US 5,443,461; US 5,456,679; US 5,460,826; US 5,462,741; US 5,462,745; US 5,489,281; US 5,499,979; US 5,500,222; US 5,512,293; US 5,512,299; US 5,529 / 787; US 5,531,736 US 5,532,003; US 5,533,971; US 5,534,263; US 5,540,912; US 5,543,156; US 5,571,525; US 5,573,503; US 5,591,124 US 5,593, 695; US 5,595,759; US 5,603,954; US 5,607,696; US 5,609,885; US 5,614,211; US 5,614,578; US 5,620,705; US 5,620,708; US 5,622,530; US 5,622,944; US 5,633,011; US 5,639,477; US 5,660,861; US 5,667,804; US 5,667,805; US 5,674,895; US 5,688,518; US 5,698,224; US 5,702,725; US 5,702,727; US 5,707,663; US 5,713,852; US 5,718,700 US 5,736,580 US 5,770,227 US 5,780,058 US 5,783,213 US 5,785,994; US 5,795,591; US 5,811,465; US 5,817,624 US 5,824,340 US 5,830,501; US 5,830,502 US 5,840,754 US 5,858,407 US 5,861,439 US 5,863,558 US 5,876,750 US 5,883,135 US 5,897,878 US 5,904,934 US 5,904,935 US 5,906,832 US 5,912,268 US 5,914,131 US 5,916,582 US 5,932,547 US 5,938,654 US 5,941,844 US 5,955,103 US 5,972,369 US 5,972,370 US 5,972,379 US 5,980,943 US 5,981,489 US 5,983,130 US 5,989 / 590 US 5,995,869 US 5,997,902 US 6,001,390 US 6,004,309 US 6,004,578 US 6,008,187 US 6,020,000 US 6,034,101 US 6,036,973 US 6,039,977 US 6,057,374 US 6,066,619 US 6,068,850 US 6,077,538 US 6,083,190 US 6,096,339 US 6,106,845 US 6,110,499; US 6,120,798; US 6,120,803; US 6,124,261 US 6,130,200; US 6,146,662; US 6,153,678; US 6,174,547; US 6,183,466; US 6,203,817; US 6,210,712; US 6,210,713; US 6,224,907; US 6,235,712; US 6,245,357; US 6,262,115; US 6,264,990; US 6,267,984; US 6,287,598; US 6,289,241; US 6,331,311; US 6,333,050; US 6,342,249; US 6,346,270; US 6365183; US 6,368,626; US 6,387,403; US 6,419,952; US 6,440,457; US 6,468,961; US 6,491,683; US 6,512,010; US 6,514,530; US 6534089; US 6,544,252; US 6,548,083; US 6,551,613; US 6,572,879; and US 6,596,314. Other examples of controlled release formulations, tablets, dosage forms, and drug delivery systems that are suitable for use with the present invention are described in the following applications of published US patents and PCT applications assigned to ALZA Corporation: US 20010051183; WO 0004886; WO 0013663; WO 0013674; WO 0025753; WO 0025790; WO 0035419; WO 0038650; WO 0040218; WO 0045790; WO 0066126; WO 0074650; WO 0119337; WO 0119352; WO 0121211; WO 0137815; WO 0141742; WO 0143721; WO 0156543; WO 3041684; WO 03041685; WO 03041757; WO 03045352; WO 03051341; WO 03053400; WO 03053401; WO 9000416; WO 9004965; WO 9113613; WO 9116884; WO 9204011; WO 9211843; WO 9212692; WO 9213521; WO 9217239; WO 9218102; WO 9300071; WO 9305843; WO 9306819; WO 9314813; WO 9319739; WO 9320127; WO 9320134; WO 9407562; WO 9408572; WO 9416699; WO 9421262; WO 9427587; WO 9427589; WO 9503823; WO 9519174; WO 9529665; WO 9600065; WO 9613248; WO 9625922; WO 9637202; WO 9640049; WO 9640050; WO 9640139; WO 9640364; WO 9640365; WO 9703634; WO 9800158; WO 9802169; WO 9814168; WO 9816250; WO 9817315; WO 9827962; WO 9827963; WO 9843611; WO 9907342; WO 9912526; WO 9912527; WO 9918159; WO 9929297; WO 9929348; WO 9932096; WO 9932153; WO 9948494; WO 9956730; WO 9958115; and WO 9962496. Another drug delivery technology suitable for use in the present invention is that disclosed by DepoMed, Inc. in U.S. Patent No. 6,682,759, which discloses a method for manufacturing a pharmaceutical tablet for oral administration by combining both of the modes of immediate release and prolonged release of drug supply. The tablet according to the method comprises a prolonged release drug core and an immediate release drug coating or layer, which may be insoluble or sparingly soluble in water. The method limits the particle diameter of the drug in the immediate release coating or layer to 10 microns or less. The coating or layer is either of the particles themselves, applied as an aqueous suspension, or a solid composition containing the drug particles incorporated in a solid material that rapidly disintegrates in the gastric fluid. Andrx Corporation has also developed the drug delivery technology suitable for use in the present invention which includes: 1) a pulsed pellet delivery system ("PPDS"); 2) an osmotic tablet system of individual composition ("SCOT"); 3) a solubility modulation hydrogel system ("SMHS"); 4) a delayed pulsatile hydrogel system ("DPHS"); 5) a stabilized pellet supply system ("SPDS"); 6) a granulated modulation hydrogel system ("GMHS"); 7) a pellet tablet system ("PEL "); 8) a porous tablet system ("POR "); and 9) a stabilized tablet delivery system ("STDS"). PPDS uses pellets that are coated with specific polymers and agents to control the release rate of the microencapsulated drug and is designed for use with drugs that require pulsed release. SCOT uses various osmotic modulating agents as well as polymeric coatings to provide a zero order drug release. SMHS uses a gel-based dosing system that avoids the "initial discharge effect" commonly observed with other sustained-release hydrogel formulations and that provides sustained release without the need to use coatings or special structures that are added to the cost of the manufacture. DPHS is designed for use with hydrogel matrix products characterized by an initial zero-order drug release followed by a rapid release that is achieved by mixing selected hydrogel polymer to obtain a delayed pulse. SPDS incorporates a drug pellet core and a protective polymer outer layer, and is designed specifically for unstable drugs, while GMHS incorporates hydrogel and binder polymers with the drug and forms granules that are pressed into a tablet. PELTAB provides controlled release by using a water insoluble polymer to coat crystals or pellets of discrete drugs to allow them to resist the action of fluids in the gastrointestinal sense, these coated pellets are then compressed into tablets. PORTAB provides controlled release by incorporating an osmotic core with a continuous polymer coating and a water soluble component that expands the core and creates microporous channels through which the drug is released. Finally, STDS includes a double layer coating technique which avoids the need to use a coating layer to separate the enteric coating layer from the omeprazole core. Examples of controlled release formulations, tablets, dosage forms and drug delivery systems, which are suitable for use with the present invention are described in the following North American patents assigned to Andrx Corporation: US 5,397,574; US 5,419,917; US 5,458,887; US 5,458,888; US 5,472,708; US 5,508,040; US 5,558,879; US 5,567,441; US 5,654,005; US 5,728,402; US 5,736,159; US 5,830, .503; US 5,834,023; US 5,837,379; US 5,916,595; US 5,922,352; US 6,099,859; US 6,099,862; US 6,103,263; US 6,106,862; US 6,156,342; US 6,177,102; US 6,197,347; US 6,210,716; US 6,238,703; US 6,270,805; US 6,284,275; US 6,485,748; US 6,495,162; US 6,524,620; US 6,544,556; US 6,589,553; US 6,602,522 and US 6,610,326. Examples of controlled release formulations, tablets, dosage forms and drug delivery systems, which are suitable for use with the present invention are described in the following published U.S. and PCT patent applications assigned to Andrx Corporation: US20010024659; US20020115718; US20020156066; WO0004883; WO0009091; WO0012097; WO0027370; WO0050010; WO0132161; WO0134123; WO0236077; WO0236100; WO02062299; WO02062824; WO02065991; WO02069888; WO02074285; WO03000177; WO9521607; W09629992; WO9633700; WO9640080; W09748386; W09833488; W09833489; WO9930692; W09947125 and WO9961005. Some other examples of drug delivery procedures focus on the non-oral drug delivery, providing the parenteral, transmucosal and topical delivery of proteins, peptides and small molecules. For example, the Atrigel® drug delivery system marketed by Atrix Laboratories Inc. comprises biodegradable polymers, similar to those used in biodegradable sutures, dissolved in biocompatible carriers. These pharmaceutical substances can be mixed in a liquid supply system at the time of manufacture or, depending on the product, can be added with a professional at the time of use. Injecting the liquid product subcutaneously or intramuscularly through a small-gauge needle, or placing the tissue accessible through a cannula, causes the displacement of the carrier with water in the tissue fluids, and a subsequent precipitate that is formed from the polymer in a solid film or implant. The drug encapsulated within the implant is then released in a controlled manner as the polymer matrix biodegrades for a period ranging from days to months. Examples of such drug delivery systems include Eligard®, Atridox® / Doxirobe®, Atrisorb®, FreeFlowTm / Atrisorb®-D FreeFlow from Atrix, bone growth products and others as described in the following North American and PCT patent applications. published by Atrix Laboratorios Inc.: US RE37950; US 6,630,155; US 6,566,144; US 6,610,252; US 6,565,874; US 6,528,080; US 6,461,631; US 6,395,293; US 6,261,583; US 6, 143/314; US 6,120,789; US 6,071,530; US 5,990,194; US 5,945,115; US 5,888,533; US 5,792,469; US 5,780,044; US 5,759,563; US 5,744,153; US 5,739,176; US 5,736,152; US 5,733,950; US 5,702,716; US 5,681,873; US 5,660,849; US 5,599,552; US 5,487,897; US 5,368,859; US 5,340,849; US 5,324,519; US 5,278,202; US 5,278,201; US20020114737, US20030195489; US20030133964; US 20010042317; US20020090398; US20020001608 and US2001042317. Atrix Laboratories Inc. also markets technology for non-oral transmucosal drug delivery over a period of minutes to hours. For example, the "BEMA ™ (Bioretible Muco-adhesive Disc)" drug delivery system of Atrix comprises preformed bioerodible discs for local or systemic delivery Examples of such drug delivery systems include those described in US Pat. 6,245,345 Other drug delivery systems marketed by Atrix Laboratories Inc. focus on topical drug delivery For example, SMP ™ (Solvent Particule System) allows topical delivery of highly water insoluble drugs. The controlled amount of a dissolved drug penetrates the epidermal layer of the skin by combining the dissolved drug with the microparticle suspension of the drug.The SMP ™ system works in stages whereby: 1) the product is applied to the surface of the skin; 2) the product near the follicles is concentrated in the skin's forum; 3) the drug is easily divided into skin oils; and 4) the drug diffuses throughout the area. In contrast, MCA® (Mucocutaneous Absorption System) is a topical water-resistant gel that provides sustained drug delivery. MCA® forms a persistent film for either wet or dry surfaces where: 1) the product is applied to the skin or mucosal surface; 2) the product forms a persistent moisture resistant film; and 3) the adhering film provides sustained release of the drug for a period of hours to days. Still another product, BCP ™ (Biocompatible Polymer System) provides a non-cytotoxic or liquid gel that is applied as a protective film for wound healing. Examples of these systems include Orajel®-Ultra Mouth Sore Medicine as well as those described in the following patents and published US applications assigned to Atrix Laboratories Inc .: US 6,537,565; US 6,432,415; US 6,355,657; US 5,962,006; US 5,725,491; US 5,722,950; US 5,717,030; US 5,707,647; US 5,632,727 and US20010033853. Additional formulations and compositions available from Teva Pharmaceutical Industries Ltd. Warner Lambert & Co. and Godecke Aktienge'sellshaft which include gabapentin and which are useful in the present invention, include those described in the following North American patents and US patent and published PCT applications: US 6,531,509; US 6,255,526; US 6,054,482; US2003055109; US2002045662; US2002009115; WO 01/97782; WO 01/97612; EP 2001946364; W099 / 59573 and WO 99/59572. Additional formulations and compositions including oxybutynin and which are useful in the present invention include those as described in the following North American patents and the published US and PCT patent applications: US 5,834,010; US 5,601,839 and US 5,164,190. Dosage and Administration The concentration of the active agent in any of the dosage forms mentioned in the foregoing and the compositions may vary by a large amount, and will depend on a large number of factors, including the type of composition or dosage form, the corresponding mode of administration, the nature and activity of the specific active agent and the proposed release profile of the drug. Preferred dosage forms contain a unit dose of active agent, i.e., an individual therapeutically effective dose. For creams, ointments, etc., a "unit dose" requires a concentration of active agent that provides a unit dose in a specific amount of the formulation to be applied. The unit dose of any active agent will, of course, depend on the active agent and the mode of administration. For the active agents of the present invention (including a modulator of the calcium channel subunit qtd in combination with a compound with modulatory effects of smooth muscle), the unit dose for. oral, transmucosal, topical, transdermal and parenteral administration will be in the range of about 1 ng to about 10,000 mg, about 5 ng to about 9 -1, 5 ~ J0w0u m ± LLy, about 10 ng to about 9,000 mg, about 20 ng to about 8,500 mg, about 30 ng to about 7,500 mg, about 40 ng to about 7,000 mg, about 50 ng to about 6,500 mg, about 100 ng to about 6,000 mg, about 200 ng to about 5,500 mg, about 300 ng to about 5,000 mg, about 400 ng to about 4,500 mg, about 500 ng to about 4,000 mg, about 1 μg to about 3,500 mg, about 5 μg to about 3,000 mg, about 1 μg to about 3,500 mg, about 10 μg to about 2.600 mg, about 20 μg to about 2.575 mg, about 30 μg a about 2,550 mg, about 40 μg to about 2,500 mg, about 50 μg to about 2,475 mg, about 100 μg to about 2,450 mg, about 200 μg to about 2,425 mg about 300 μg to about 2,000 mg about 400 μg to about 1,175 mg approximately 500 μg to about 1,150 mg, about .5 mg to about 1,125 mg, about 1 mg to about 1,100 mg, about 1.25 mg to about 1.075 mg, about 1.5 mg to about 1.050 mg, about 2.0 mg to about 1.025 mg, about 2.5 mg to about 1,000 mg, about 3.0 mg to about 975 mg, about 3.5 mg to about 950 mg, about 4.0 mg to about 925 mg, about 4.5 mg to about 900 mg, about 5 mg to about 875 mg, about 10 mg a approximately 850 mg, approximately 20 m about 825 mg, about 30 mg to about 800 mg, about 40 mg to about 775 mg, about 50 mg to about 750 mg, about 100 mg to about 725 mg, about 200 mg to about 700 mg, about 300 mg to about 675 mg, approximately 400 mg to approximately 650 mg, approximately 500 mg or approximately 525 mg to approximately 625 mg. Alternatively, for the active agents of the present invention (including a modulator of the calcium channel subunit oi2d in combination with a compound with modulatory effects of smooth muscle), the unit dose for oral, transmucosal, topical, transdermal and parenteral administration will be equal to or greater than about 1 ng, about 5 ng, about 10 ng, about 20 ng, about 30 ng, about 40 ng, about 50 ng, about 100 ng, approximately 200 ng, approximately 300 ng, approximately 400 ng, approximately 500 ng, approximately 1 μg, approximately 5 μg, approximately 10 μg, approximately 20 μg, approximately 30 μg, approximately 40 μg, approximately 50 μg, approximately 100 μg , about 200 μg, about 300 μg, about 400 μg, about 500 μg, about .5 mg, about 1 mg, about 1.25 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1100 mg, about 1125 mg, about 1150 mg, about 1175 mg, about 1200 mg, about 1225 mg, about 1250 mg, about 1275 mg, about 1300 mg, about 1325 mg, approximately 1350 mg, approximately 1375 mg, approximately 1400 mg, ap about 1425 mg, about 1450 mg, about 1475 mg, about 1500 mg, about 1525 mg, about 1550 mg, about 1575 mg, about 1600 mg, about 1625 mg, about 1650 mg, about 1675 mg, about 1700 mg, about 1725 mg, approximately 1750 mg, approximately 1775 mg, approximately 1800 mg, approximately 1825 mg, approximately 1850 mg, approximately 1875 mg, approximately 1900 mg, approximately 1925 mg, approximately 1950 mg, approximately 1975 mg, approximately 2000 mg, approximately 2025 mg, about 2050 mg, about 2075 mg, about 2100 mg, about 2125 mg, about 2150 mg, about 2175 mg, about 2200 mg, about 2225 mg, about 2250 mg, about 2275 mg, about 2300 mg, about 2325 mg, about 2350 mg, approximately 2375 mg, approximately 2400 mg, ap about 2425 mg, about 2450 mg, about 2475 mg, about 2500 mg, about 2525 mg, about 2550 mg, about 2575 mg, about 2600 mg, about 3000 mg, about 3500 mg, about 4000 mg, about 4500 mg, about 5000 mg, approximately 5500 mg, approximately 6000 mg, approximately 6500 mg, approximately 7000 mg, approximately 7500 mg, approximately 8000 mg, approximately 8500 mg, approximately 9000 mg or approximately 9500 mg. For the active agents of the present invention (including a calcium channel modulator a2d subunit in combination with a compound with smooth muscle modulating effects), the unit dose for intrathecal administration will be in the range of about 1 fg to about 1 mg , approximately 5 fg to approximately 500 μg, about 10 fg to about 400 μg, about 20 fg to about 300 μg / about 30 fg to about 200 μg, about 40 fg to about 100 μg / about 50 fg to about 50 μg, about 100 fg to about 40 μg / about 200 fg to about 30 μg / about 300 fg to about 20 μg, about 400 fg to about 10 μg / about 500 fg to about 5 μg / about 1 pg to about 1 μg, about pg to about 500 ng, about 10 pg to about 400 ng, about 20 pg to about 300 ng, about 30 pg to about 200 ng, about 40 pg to about 100 ng, about 50 pg to about 50 ng, about 100 pg at about 40 ng, about 200 pg at about 30 ng, about 300 pg at about 20 ng, about 400 pg at about 10 ng, about 500 pg at about 5 ng. Alternatively, for the active agents of the present invention (including a calcium channel modulator 2d subunit in combination with a compound with smooth muscle modulating effects), the unit dose for intrathecal administration will be equal to or greater than about 1 fg, approximately 5 fg, approximately 10 fg, approximately 20 fg, approximately 30 fg, approximately 40 fg, approximately 50 fg, approximately 100 fg, approximately 200 fg, approximately 300 fg, approximately 400 fg, approximately 500 fg, approximately 1 pg, approximately 5 pg , about 10 pg, about 20 pg, about 30 pg, about 40 pg, about 50 pg, about 100 pg, about 200 pg, about 300 pg, about 400 pg, about 500 pg, 1 ng, about 5 ng, about ng, approximately 20 ng, approximately 30 ng, approximately 40 ng, approximately 50 ng, approximately 1 00 ng, approximately 200 ng, approximately 300 ng, approximately 400 ng, approximately 500 ng, approximately 1 μg, approximately 5 μg, approximately 10 μg, approximately 20 μg, approximately 30 μg, approximately 40 μg, approximately 50 μg, approximately 100 μg , approximately 200 μg, approximately 300 μg, approximately 400 μg or approximately 500 μg. The present invention also comprises a pharmaceutical formulation comprising oxybutynin, wherein the unit dose for oral, transmucosal, topical, transdermal, and parenteral administration of oxybutynin will be of an amount equal to or less than about 5 mg, about 4.5 mg, about 4 mg. mg, about 3.5 mg, about 3 mg, about 2.5 mg, about 2 mg, about 1.5 mg, about 1.25 mg, about 1.0 mg, or about 0.5 mg. Due to the synergistic action of the calcium channel modulators 2d subunit when combined with smooth muscle modulators, the dosages of the zd subunit calcium channel modulators and the smooth muscle modulators that have been known in the art or predicted that are not effective in treating and / or alleviating the symptoms associated with painful and non-painful urinary tract disorders in patients with normal and injured spinal cord are effective when administered in accordance with the methods of the present invention. A therapeutically effective amount of a particular active agent, administered to a given individual will, of course, be dependent on a number of factors, including the concentration of the specific active agent, the composition or dosage form, the mode of administration selected, the age and the general condition of the individual being treated, the severity of the individual's condition, and other factors known to the prescribing physician. In a preferred embodiment, administration of the drug is on a basis as necessary, and does not involve the administration of the chronic drug. With an immediate release dosage form, administration as necessary may involve administration of the drug immediately prior to the start of an activity wherein suppression of the supraactive symptoms would be desirable, but will generally be in the range of about 0 minutes to about 10 hours before such activity, preferably in the range of about 0 minutes to about 5 hours before such activity, much more preferably in the range of about 0 minutes to about 3 hours before such activity. With a sustained release dosage form an individual dose can provide therapeutic efficacy for a prolonged period in the range of about 1 hour to about 72 hours, typically in the range of about 8 hours to about 48 hours, depending on the formulation . That is, the period of release can be varied by the selection and the relative amount of the particular sustained release polymers. If necessary, however, administration of the drug can be carried out within the context of a progressive dosing regimen, that is, on a weekly basis, twice a week, daily, etc. In another preferred embodiment, at least one deleterious side effect associated with the individual administration of a calcium channel modulator a2d subunit or a smooth muscle modulator is ameliorated by concurrent administration of a calcium channel modulator subunit o2d with smooth muscle modulator. For example, side effects for oxybutynin, a modulator of smooth muscle antimuscarinic, include dry mouth, sensitivity to bright light, blurred vision, dry eyes, decreased exudation, flushing, deranged stomach, constipation, and drowsiness. However, when administered in combination with a calcium channel modulator a2d subunit such as gabapentin, significantly less than each agent is needed to achieve therapeutic efficacy (eg, less than the 5 mg dose of oxybutynin currently marketed in the United States and also less than the 2.5 mg dose of oxybutynin currently marketed in Europe). Because detrimental side effects are minimized, the present invention also has the benefit of improving patient compliance. Packed Kits In another embodiment, a packaged kit containing the pharmaceutical formulation to be administered is provided, ie, a pharmaceutical formulation containing a therapeutically effective amount of a calcium channel modulator a2d subunit in combination with one or more compounds with effects Smooth muscle modulators to treat and / or relieve symptoms associated with painful and non-painful urinary tract disorders, including associated irritative symptoms in patients with normal or injured spinal cord, a container, preferably sealed, to contain the formulation during storage and before use, and instructions for carrying out drug administration in an effective manner to treat painful and non-painful urinary tract disorders, including the associated irritative symptoms in patients with normal or injured spinal cord . The instructions will typically be instructions written on a package insert and / or on a label. Depending on the type of formulation and the proposed mode of administration, the kit may also include a device for administration of the formulation. The formulation may be any suitable formulation as described herein. For example, the formulation may be an oral dosage containing a unit dosage of a selected active agent. The kit can contain multiple formulations of different dosages of the same agent. The kit may also contain multiple formulations of different active agents. The kit may contain formulations suitable for sequential use, separate or simultaneous in the treatment and / or relief of symptoms associated with disorders of the lower urinary tract, and instructions for carrying out the administration of the drug wherein the formulations are administered sequentially, separately and / or simultaneously in the treatment and / or relief of symptoms associated with lower urinary tract disorders. The kit may also contain at least one component selected from a calcium channel modulator a2d subunit and a smooth muscle modulator; a container that contains the component or components during storage and before administration; and instructions for carrying out drug administration of a calcium channel modulator subunit a2d with a smooth muscle modulator in a manner effective to treat low urinary tract disorder. Such a kit may be useful, for example, where the calcium channel modulator subunit α2d or the smooth muscle modulator is already being administered to the patient, and the additional component is to be added to the patient's drug regimen. Such a kit may also be useful where different individuals (e.g., physicians or other medical professionals) are administering the separate components of the combination of the present invention. The parts of the kit can be independently maintained in one or more containers - such as bottles, syringes, plates, cavities, blister packs or any other type of pharmaceutical packaging. Insurance Claims In general, the processing of an insurance claim for the coverage of a given medical treatment or drug therapy involves the notification of the insurance company or any other entity that has issued the insurance policy against which the claim is being presented. , in which medical treatment or drug therapy will be performed. A determination is then made as to the medical treatment the drug therapy that will be performed is covered under the terms of the insurance policy. If it is covered, the claim is then processed, which may include payment, reimbursement or application against a deductible. The present invention comprises a method for processing an insurance claim under an insurance policy for a modulator of the calcium channel subunit oi2d and an antimuscarinic or pharmaceutically acceptable salts, esters, amides, prodrugs or active metabolites thereof used in the treatment and / or relief of symptoms associated with disorders of the lower urinary tract, wherein the modulator of the calcium channel subunit a2d and the antimuscarinic or pharmaceutically acceptable salts, esters, amides, prodrugs or active metabolites thereof are administered sequentially or concurrently in different compositions. This method comprises: 1) receiving notification that treatment using the calcium channel modulator a2d subunit and the antimuscarinic or pharmaceutically acceptable salts, esters, amides, prodrugs or active metabolites thereof will be performed or notification of a prescription; 2) determine whether treatment using the calcium channel modulator subunit? Í2d and the antimuscarinic or pharmaceutically acceptable active salts, esters, amides, prodrugs or metabolites is covered under the insurance policy; and 3) processing the claim for the treatment of low urinary tract disorders using the calcium channel modulator a2d subunit and the antimuscarinic or pharmaceutically acceptable salts, esters, amides, prodrugs or active metabolites thereof, including payment, reimbursement or request against a deductible. For use in this method, a particularly preferred a2d subunit calcium channel modulator is gabapentin, while a particularly preferred antimuscarinic is oxybutynin. This method also comprises the processing of claims for and the calcium channel modulator cc2d subunit, particularly gabapentin or an antimuscarinic, particularly oxybutynin, when it has already been prescribed separately or concurrently for the treatment and / or relief of symptoms associated with the disorders of the lower urinary tract. Many modifications and other embodiments of the inventions set forth herein will come to mind to one skilled in the art to which these inventions pertain that has the benefit of the teachings presented in the foregoing descriptions and the associated drawings. Thus, it is to be understood that the inventions are not going to be limited to the specific modalities disclosed and that the modifications and other modalities are proposed to be included within the scope of the attached modalities. Although specific terms are used herein, they are used in a generic and descriptive sense only and not for purposes of limitation. EXAMPLES Methods for the Treatment and / or Relief of Symptoms Associated with Low Urinary Tract Disorders Using Modulators of the Calcium Channel Subunit cc2d with Modulators of the Smooth Muscle. The invention will also be described in the following examples, which do not limit the scope of the invention described in the claims. The following examples illustrate the effects of administering the combination of a calcium channel modulator a2d subunit and a smooth muscle modulator on bladder capacity in an irritated bladder model. It is expected that these results demonstrated the efficacy of the combination of a calcium channel modulator a2d subunit and a smooth muscle modulator for the treatment and / or relief of symptoms associated with painful and non-painful urinary tract disorders in patients. with the normal and injured spinal cord as described herein. These methods include the use of a well-accepted model for urinary tract disorders involving the bladder using intravesically administered acetic acid as described in Sasaki et al. (2002) J. Urol. 168: 1259-64 and Thor and Katafiasc (1995) J. Pharmacol. Expl tl. Ther. 274: 1014-24. Efficacy for the treatment of patients with injured spinal cord can be tested using the methods as described in Yoshiyama et al. (1999) Exp. Neurol. 159: 250-7. The present invention comprises the use of antimuscarinics except for atropine, scopolamine, and trospium chloride. It is observed that each of these compounds all contain an amine embedded in a skeleton of 8-azabicyclo [3.2.1] octan-3-ol. Example 1 - Diluted Acetic Acid Model: Gabapentin and Oxybutynin Objective and Reasoned Exposure The objective of this study was to determine the ability of a modulator of the calcium channel subunit ad in combination with a modulator of smooth muscle to reverse the reduction in bladder capacity observed after the continuous infusion of diluted acetic acid, a model commonly used for the supra-active bladder. In particular, the current study used gabapentin as an exemplary calcium channel modulator? Í2d and oxybutynin as an exemplary smooth muscle modulator. Materials and Methods Normal female rats anesthetized with urethane (1.2 g / kg) were used in this study. Groups of rats were treated with oxybutynin alone (n = 13), gabapentin only (n = ll), and corresponding combinations of respective doses of oxitubinin and gabapentin (n = ll). Subsequently, three series of markedly lower doses in different dose ratios were performed for the purposes of isobologram construction (n = 4 / group). Cumulative dose-response protocols were used with mean log increments for all studies. Drugs and Preparation The drugs were dissolved in normal saline at 1, 3 and 10 mg / ml for obibutinin and 30, 100 and 300 mg / ml for gabapentin. In these studies, the individual doses and combinations subsequently can be referred to as Low, Medium and High. Subsequent studies directed in the construction of the isobologram combined the drugs in dose combinations as shown in the table below (low, medium and high dose for each pair of drugs). The animals were dosed by the injection volume = body weight in kg. Table 1: Combinations of Dose of Isobologram (mg / kg) Model I Live Anesthetized Acute Preparation of the Animal: Female rats (250-300 kg of body weight) were anesthetized with urethane (1.2 g / kg) and a catheter filled with saline solution (PE-50) was inserted into the jugular vein for intravenous drug administration. Via a midline lower abdominal incision, a wide tip PE 50 catheter was inserted into the bladder dome for filling the bladder and recording the pressure. The abdominal cavity was moistened with solution • saline and closed by covering a thin plastic sheet in order to maintain access to the bladder for emptying purposes. Electrodes of fine silver or stainless steel wire were inserted into the external urethral sphincter (EUS) percutaneously for electromyography (EMG). Experimental Design: Saline was infused continuously at a rate of 0.055 ml / min via the bladder filling catheter for 60 minutes to obtain a baseline of low urinary tract activity (continuous cystography; CMG). After the control period, a solution of 0.25% acetic acid in saline was infused into the bladder at the same flow rate to induce bladder irritation. After 30 minutes of the AA infusion, 2 vehicle injections were made at 20 minute intervals to determine the effects of the vehicle, if any. Subsequently, increased doses of a selected active agent, or combination of agents, in increment of half log were administered intravenously at 30 minute intervals in order to build a cumulative dose-response relationship. At the end of the period of cystometry with control saline, the third vehicle, and 20 minutes after each subsequent treatment, the infusion pump was stopped, the bladder was emptied by withdrawing fluid via the infusion catheter and a Single filling cystometrogram was performed in the same proportion of flow in order to determine changes in bladder capacity caused by the irritation protocol and the subsequent intravenous drug administration. Data Analysis The bladder capacity data for each animal was normalized to "% Recovery from Irritation", and this index was used for the measurement of efficacy. Data from the experiments in which each of the drugs were administered alone were used to create theoretical populations of additive effects for each dose (low, medium and high), and these were compared using a one-sided t test (comparisons of individual doses) and by 2-way ANOVA (cross-dose) for the data of the actual combination drugs. The averages and standard deviations for each of the "corresponding dose" responses of the individual treatment (low, medium and high) were added together to estimate the average and the standard deviation of the theoretical additive populations for which to compare the current data. obtained from the combination experiments. The population of the theoretical additive effect N = (Nant? Muscarinic + N subunit modulator a2d) _ 1- P < 0.050 was considered significant. Only rats that showed a 50-90% reduction in bladder capacity in the third measurement of the vehicle when compared to pre-irritation saline control values were used for numerical analysis. The construction of the isobologram consisted of two methods, both using the same data, but plotting the results either as group averages or individual responses. When the group average data are used, the maximum common effect achieved by both drugs alone and the combinations listed in the table above was a return to 43% of the saline control bladder capacity values. When individual responses are used for both drugs alone and the combinations listed in the table above, the target value was 31% of the saline control. These low values reflect the moderate effectiveness of oxybutynin and gabapentin alone. For statistical purposes, the data were analyzed making comparisons for each drug, without considering whether it is alone or in combination. Results and Conclusions The effect of cumulative increased doses of oxitubinin (n = 13), gabapentin (n = ll) and their corresponding combinations (eg, dose 1 for the combination was 30 mg / kg gabapentin and 1 mg / kg of oxybutynin; n = ll) on the capacity of the bladder is represented in Figure 1. The data are normalized to the saline controls and are presented as Average ± SEM. The effect of cumulative increased doses of oxybutynin (n = 13), gabapentin (n = ll) and their corresponding combinations (eg, Dose 1 for the combination was 30 mg / kg gabapentin and 1 mg / kg) of oxybutynin; n = ll) on the bladder capacity (normalized to% Recovery from Irritation) are shown in Figure 2. Note that the combination of drugs produced a greater effect than the additive in the Low doses (P = 0.0031) and Mean (P = 0.0403), in the reduction in bladder capacity caused by continuous intravesical exposure to dilute acetic acid. Synergy is also suggested by significant differences between the additive and combination effects by 2-way ANOVA (P = 0.0046). The data is presented as Average ± SEM. The results of the isobologram studies as determined by using the group averages to determine effective doses are represented in Figure 3. Using this technique, the maximum common effect for any drug was only returned to 43% of the saline control. The line that connects the two axes in the effective dose for each drug only represents the theoretical additivity. The three isolated points grouped in the lower left field of the graph below the additivity line represent the dose ranges of three sets of experiments using low dose ratios of drug combinations. As can be easily visualized by this isobologram, remarkably lower doses of both drugs were required in combination to reach the same endpoint as any drug alone. A maximum common effect of the individual animals was determined (a return to 31% of the saline control values; Figure 4). Using this procedure, it was possible to show that there were no overlaps between doses of oxybutynin alone than those used in the combination studies of the isobologram in terms of the standard deviation, and that all effective oxybutynin combination intervals were significantly less than the interval of oxybutynin alone. Similarly, the effective ranges of gabapentin used in the combinations were significantly lower than when only gabapentin was used. The data is presented as Average + SD. The ability of a calcium channel modulator a2d subunit in combination with a smooth muscle modulator to produce a dramatic reversal in the reduction induced by acetic acid irritation in the bladder capacity strongly indicates the effectiveness in the form of mammalian disorders. of the urinary tract under painful and non-painful and irritative symptoms. associated in patients with normal and injured spinal cord. In addition, the combination of a modulator of the calcium channel subunit a_d and a smooth muscle modulator produced a synergistic effect that was larger than would be expected if the effects were simply additive, and also demonstrated efficacy using amounts of the individual agents that they are much smaller than those that would be expected to produce an effect if the agents were administered individually. Example 2 - Pharmacokinetic Analysis: Gabapentin and Oxybutynin Objective and Reasoned Exposure The purpose of this study was to determine the concentrations of gabapentin, oxybutynin and desethyl oxybutynin in plasma samples from rats for a period of 2 hours after either 3 mg / kg of oxybutynin, 100 mg / kg gabapentin, or the combination of these two drugs at those doses using a liquid chromatography with the tandem mass spectrometric detection method (LC / MS / MS). Materials and Methods Female rats anesthetized with urethane (1.2 g / kg) used this study. 'Groups of rats were treated with oxybutynin alone (n = 6), gabapentin only (n = 8) and respective corresponding dose combinations of oxybutynin and gabapentin (n = 8). Drugs and Preparation The drugs were dissolved in normal saline at 3 mg / ml for oxybutynin and 100 mg / ml for gabapentin. The animals were dosed by the injection volume equal body weight in kg. In Vivo Preparation Pharmacokinetics Preparation of Animals: Female rats (250-300 g of body weight) were anesthetized with urethane (1.2 g / kg) and a catheter filled with saline (PE-50) was inserted into the jugular vein for the administration of intravenous drug. Experimental Design: Plasma samples (200 μl; K3 EDTA) were taken on ice at 4 time points (15, 30, 60 and 120 minutes) after intravenous drug administration. The samples were rotated at 1600 RPM for 7 minutes, the plasma was removed and stored at -80 ° C until chromatographic analysis. Pharmacokinetic Chromatographic Analysis Internal Standards: Oxybutynin-Du chloride and baclofen were used as internal standards. Sample Analysis LC / MS / MS Summary of the Method Preparation of the Extract Solution Preparation of Work Solutions Intermediate Standards Internal Standards Pre-aration of Calibration Standards All extract solutions and the internal work standard were stored at 2-8 ° C. The initial standard was stored frozen at approximately -20 ° C. Extraction Procedure Include the solvent blank, a white matrix (double white) and a Control 0 (white matrix dotted with IS) with the calibration curve. Aliquot 50.0 μL of control rat plasma, calibration standards or study sample, as appropriate, to an elution plate of 96 cavities At Control 0, the samples of -calibration and study, additional 200 μL of the work-IS solution. To the white solvent and white matrix, add 200 μL of acetonitrile. Mix all the tubes in a vortex for 30 seconds Centrifuge at 2800 rpm for 10 minutes. Transfer the supernatant to a second 96-well elution plate. 7 Inject 20 μL onto the LC / MS / MS system for analysis. Chromatographic Conditions Spectrometric conditions of mass (Sciex) Exploration Parameters Oxibutinin Desethyloxybutynin Gabapentin Baclofen Oxybutynin-Dn Ion Precursor 358. 4 330. 4 172.3 214. _ 368. 5 Ion Product 142.2 96.2 137.1 151.1 142.2 Time 150 150 150 50 50 Residence (ms) DP-Potential of 42 32 27 27 42 Ungrouping (V) FP-Potential of 115 100 80 115 Focusing (V) CE- Energy 34 24 23 36 Collision (eV) CXP- Potential of 15 16 10 Collision Cell Output (V) IS-Ion Voltage 2200 Dew (V) TEM-Turbo Gas 500 Temperature (° C) NEB-Gas 12 CUR-Gas Curtain Nebulizer Calculations: Calculations were performed using Excel Version 8.0e. Some reporter values may differ in the last digit reported from the values calculated directly from the reporting tables due to the rounding that has been applied. Pharmacokinetic analysis: The maximum concentration (Cmax) in the rat plasma and the time to reach the maximum concentration (Tmax) were obtained by visual inspection of the pure data. The calculated pharmacokinetic parameters included the average life time (t? / 2), for the maximum plasma concentration (Tmax), area under the concentration curve of a time from time 0 to the last point of time (AUCo-t) area under the concentration-time curve from 0 to infinity (? UC0 ~~), volume of distribution (Vz) and evacuation (CL). Pharmacokinetic parameters were calculated using WinNonlin Professional Edition (Pharsight Corporation, Version 3.3). Results and Conclusions For gabapentin (Table 2), the elimination phase of the concentration profiles against time was not well defined. Based on the comparison of the Cmax and AUC0-t data, it was presented that there is no appreciable difference between the oxybutynin (Oxi) group and the combination (Com) group. No evidence of drug-drug interaction between oxybutynin and gabapentin was found in the current study design. For oxybutynin (Table 3), the pharmacokinetic parameters (Cmax, AUC0-t / AUC0- ~, t? / 2, Vz and CL) obtained from the combination group (Com) were not shown to be appreciably different from those of the group of oxybutynin (Oxi). No evidence of drug-drug interaction between oxybutynin and gabapentin was found with the current study design. For desetil oxybutynin (Table 4), the phase of elimination of the concentration profile against time was not well defined. However, based on the comparison of the data of Cma__ and AUC0-t / it was again presented that there is no appreciable difference between the oxybutynin group (Oxi) and the combination group (Com). The results of the pharmacokinetic study indicate that the pharmacokinetic influences of one drug on the other does not take into account the synergistic nature of the oxybutynin-gabapentin combination "as observed in Example 1. That is, the synergistic nature of the positive effect of The combination of low urinary tract function is not due to any pharmacokinetic interaction Table 2 Pharmacokinetic parameters for gabapentin in rat plasma Dosage level Qax t »_ AUC« AUC *. tw Vx CL Animal Treatment (mg / kg) (n ^? NL) (minutes) (___ B * n_ / mL) (pjm * pgímL) (minutes) (njI? G) (ml mm / kg) Com 7 100 1.13EW5 60 1.26E + 07 NC NC NC NC Com - 8 100 1.01BHJ5 30 1.08E + 07 4.59EH) 7 303 951 2.18 Cora 9 100 933EWJ4 15 1.05E + 07 7.06EW1 519 1060 1.42 Csm 10 100 - 1.03E-W5 15 8.76W-06 ís pn 973 928 6.61 Cam 11 100 1.56E + 05 60 I? OE + 07 NC NC NC NC Com 20 100 1.00EHJ5 15 1.07B + 07 NC NC NC NC ' Ccpn 23 100 1.12E405 15 1.10EHJ7 439E + 07 296 975 228 • Com 24 100 1.03E 05 30 1.16BH17 NC NC NC NC Average 1.10E + 05 1.13E 07 439E + 07 .304 978 3.12 SD 1-96B-W4 1-56BHÍ6 2.27E 07 172 57.4 236 Gab 4 100 1.07BKJ5 15 1.25E + 07 NC NC NC NC Gab 5 100 1.12E + 05 15 1.02E + 07 1.95E407 116 857 5.12 Gab 6 100 1? 7W05 15 8.56E + 06 1 7E 07 86.2 910 732 Gab 12 100 Í.10E * 05 15 1.01E + 07 2.19E + 07 135 890 4.57 Gab 13 100 9.52E + 04 15 8.19BHW 1.44E + 07 99A 996 6.95 Gab 14 100 1.23E + 05 120 1.28E + 07 NC NC NC NC Gab 17 100 * 3.45BH) 1 120 * 2.12BH »NC NC NC NC Gáb 21 100 3-59 BKW 30 3.80E + 06 1.16BKI7 205 2555 8.63 Average 9.86B + 04 9.45E + 06 1.62B + 07 128 1242 6.52 SD 2.88E-KJ4 3.05B + 06 432E 06 46.7 736 1.66 AUCr Area under the concentration curve in the plasma - time to infinity. AUCo- Area under the concentration curve in the plasma- time until the last sampling time with medial concentrations. CL Evacuation. ma: Concentration in the maximum plasma. NA Not applicable NC Not calculated due to insufficient elimination phase data. SD Standard deviation. tl / 2 Average elimination half-life Tp Time for maximum concentration. Volume of distribution. Missing. Excluded from the mean and SD calculations. Table 3 Pharmacokinetic parameters for oxybutynin in rat plasma Dosage Level T __? _ AUQK - AUQ * •: Ua Vr CL Animal Treatment Cmgflcg) (ng / mL) (minutes) (n? RtigfaiL) (-tró * ngftrjL) (minutes) (ml? G) (trüJpán / k?) Com 7 3 320 15 22152 28177 24.6 3774 106 Com 8 3 360 15 20737 23114 393 7363 130 Com 9 3 248 15 16201 19116 45.5 10301 157 Com 10 3 316 15 18387 20541 39.9 8411 146 Com 11 3 282 15 16057 18295 43.3 10252 164 Com 20 3 367 15 21889 26725 53.0 8590 112 Com 23 3 342 15 19405 21702 41.5 8270 138 Com 24 3 295 15 17222 19529 41.2 9136 154 Media 316 19006 22150 41.0 8262 138 SD 40.4 2435 3624 7.97 2069 20i > Oxi 1 3 22S 15 15566 21438 72.8 14701 140 Oxi. 2 3 448 15 24555 28547 55.6 8425 105 Oxi 3 3 238 15 12865 14181 39.8 12158 212 Oxi '15 3 217 15 15880 20477 56.8 12004 147 Oxi 16 3 419 15 23333 24944 325 5632 120 Oxi 18 3 '426 15 28295 38044 66.9 7612 78.9 Media 329 20082 24605 54 10089 134 SD 112 6135 8149 155 3405 453 AUCo- ~ Area under the concentration curve in the plasma-time to infinity. AUCo-t Area under the concentration curve in the plasma - time until the last sampling time with measurable concentrations. CL Evacuation. Cmax Maximum plasma concentration. NA Not applicable NC Not calculated due to insufficient elimination phase data. SD Standard deviation. ti / 2 Average elimination life observed Tma Time for maximum concentration. Vz Volume of distribution. Table 4 Parameters Pharmacokinetics for desetil oxybutynin in rat plasma Dosage level cu * AüfCo. . AÜC * _ tía V.. CL Treatment Asj? Eaal (mgfcg) (ngfcjL) • (minutes) (p ?? * ng / mL) (p? Rigid) (minutes) (ml? C) (mL / mm kf.

Csm 3 1.19 15 68.0 471 266 2444603 6370 Com 8 3 1.15 15 65.5 495 292 2551693 6066 Com 9 3 157 30 176 877 365 1801875 3420 Com 10 3 1.71 15 163 .404 167 1788610 7426 Com 11 3 1.47 15 80.9 301 133 1907790 9965 Com 20 3 3.84 15 345 880 158 776714 3408 Com 23 3 3.23 15 264 493 113 992758 6088 Com 24 3 1.80 15 177 442 160 1563846 6788 Media 2.00 168 545 207 1728486 6191 SD 0.99 99.1 215 89.7 621739 2125 Oxi 1 3 3.6 15 306 716 158 954133 4191 Oxi 2 3 155 15 47.7 99 32.0 1392698 30168 Oxi 3 3 1.7 15 53 92 24.4 1142356 32463 Ox? 15 3 1.18 60 69.7 NC NC NC NC Oxi 16 3 1.59 15 83.9 247 100 1754810 12124 Oxi 18 3 2.81 120. 306 NC NC NC NC Media 2.07 144 289 78.6 1310999 19737 SD 0.93 126 293 62.9 346139 13789 AUC0 ~ «Area under the concentration curve in the plasma- time to infinity. AUCo-t Area under the concentration curve in the plasma-time to the last t-time sampling with measurable concentrations. CL Evacuation. Cmax Maximum plasma concentration. NA Not applicable NC Not calculated due to insufficient elimination phase data. SD Standard deviation. ti / 2 Average elimination half-life Tmax Time for maximum concentration. Vz Volume of distribution. Example 3 - Diluted Acetic Acid Model: Pregabalin and Oxibutinin Objective and Reasoned Exposure The objective of this study was to determine the ability of a calcium channel modulator subunit a_.d in combination with a modulator of smooth muscle to reverse the reduction in the Bladder capacity observed after continuous infusion of diluted acetic acid as a model commonly used for the supra-active bladder. In particular, the current study used pregabalin as an exemplary α2d subunit calcium channel modulator and oxybutynin as an exemplary smooth muscle modulator.

Materials and Methods Normal female rats anesthetized with urethane (1.2 g / kg) used this study. Groups of rats were treated with oxybutynin alone, pregabalin only, and respective corresponding dose combinations of oxybutynin and pregabalin. Drugs and Preparation In a series of studies, the drugs were dissolved in normal saline at 1, 3 and 10 mg / ml for oxybutynin and 10, 30 and 100 mg / ml for pregabalin. In these studies, individual doses and combinations can be subsequently referred to as Low, Medium and High. The animals were dosed in injection volume = body weight in kg. In another series of studies, the drugs were dissolved in normal saline at 0.625, 1.25, 2.5, 5.0 and 10 mg / ml for oxybutynin and 3.75, 7.5, 15, 30 and 60 mg / ml for pregabalin. In these studies, the individual doses and combinations can be subsequently referred to as Low, Medium Low, Medium, Medium High and High. The animals were dosed in injection volume = body weight in kg. In Vivo Model Anesthetized Acute Preparation of Animals: Female rats (250-300 g of body weight) were anesthetized with urethane (1.2 g / kg) and a catheter filled with saline (PE-50) was inserted into the jugular vein for intravenous drug administration. Via a midline lower abdominal incision, a wide tip PE 50 catheter was inserted into the bladder dome for filling the bladder and for recording the pressure. The abdominal cavity was moistened with saline and closed by covering it with a thin plastic sheet, in order to maintain access to the bladder for emptying purposes. Electrodes of fine silver or stainless steel wire were inserted into the external urethral sphincter (EUS) percutaneously for electromyography (EMG). Experimental Design: Saline was infused continuously at a rate of 0.055 ml / min via the bladder filling catheter for 60 minutes to obtain a baseline of low urinary tract activity (continuous cystometry; CMG). After the control period, a solution of acetic acid 0.25% saline was infused into the bladder at the same flow rate APRA induce bladder irritation. After 30 minutes of the AA infusion, 3 vehicle injections were made in an interval of 20 minutes to determine the effects of the vehicle, if any. Subsequently, increased doses of a selected active agent, or combination of agents, in half log increments were administered intravenously at 30 minute intervals in order to build a cumulative dose-response relationship. At the end of the control saline cistometry period, the third vehicle, and 20 minutes after each subsequent treatment, the infusion pump was stopped, the bladder was emptied by withdrawing the fluid via the infusion catheter and a single filling cystometrogram was performed at the same proportion of flow in order to determine changes in bladder capacity caused by the subsequent irritation protocol and intravenous drug administration. Data Analysis The bladder capacity data for each animal was normalized to "% Recovery from Irritation", and this index was used as the measure of effectiveness. Data from the experiments in which each of the drugs were administered alone were used to create theoretical populations of additive effects for each dose (low, medium and high), and these were compared by the one-sided test (dose comparisons). Individuals) and through 2-Way ANOVA (combined doses) for the current combination drug data. The averages and standard deviations of each "corresponding dose" responses of the individual treatments (low, medium and high) were added together to estimate the average of the standard deviations of the stubborn adhesive populations for which they are compared to the current obtained data. of the combination experiments. The population of individual theoretical additive effect (Nantimuscarinic + N subunit modulator a2d) -1. P <0.050 was considered significant. Only the rats that showed a 50-90% reduction in bladder capacity in the third measurement of the vehicle when compared to the pre-irritation saline control values were used for the numerical analysis. Results and Conclusions The effect of cumulative increased doses of oxybutynin (n = 13), pregabalin (n = 7) and corresponding combinations (eg, dose 1 for the combination was 10 mg / kg preegabalin and 1 mg / kg oxybutynin, n = 9) on the bladder capacity is represented in Figure 5. The data are normalized to the saline controls and are represented as Average ± SEM. The effect of cumulative increased doses of oxybutynin (n = 13), pregabalin (n = 7) and corresponding combinations (eg, dose 1 for the combination was 10 mg / kg pregabalin and 1 mg / kg oxybutynin; 9) on the capacity of the bladder (normalized to% Recovery from Irritation) is represented in Figure 6. The data are presented as Average ± SEM. Note that the combination of drugs produced a greater effect than the additive in the doses Low (P = 0.0386), Mean (P = 0.0.0166) and Akta (P = 0.0098), on the reduction in the capacity of the bladder caused by continuous intravesical exposure to dilute acetic acid. The synergy is also suggested by the significant difference between the additive and combination effects by 2-way ANOVA (P = 0.0004). The effect of cumulative increased doses of oxybutynin (n = 4), pregabalin (n = 7) and corresponding combinations (eg, Dose 1 for the combination was 3.76 mg / kg pregabalin and 0.625 mg / kg oxybutynin; = 4) on the capacity of the bladder is represented in Figure 7. The data are normalized to saline controls and are presented as Average ± SEM. The effect of increased cumulative doses of oxybutynin (n = 4), pregabalin (n = 7) and their corresponding combinations (eg, Dose 1 for the combination was 3.75 mg / kg of pregabalin and 0.625 mg / kg of oxybutynin; n = 4) on the capacity of the bladder (normalized to% Recovery from Irritation) is represented in Figure 8. The data are presented as Average ± SEM. Note also that the combination of drugs produced a greater effect than the additive in the Medium High (P = 0.04) and High doses (P = 0.004), on the reduction in bladder capacity caused by continuous intravesical exposure to dilute acetic acid. Synergy is also suggested by significant differences between the additive and combination effects by 2-way ANOVA (P = 0.0037). The ability of a modulator of the calcium channel subunit oi2d in combination with a smooth muscle modulator to produce a dramatic reversal in the reduction induced by acetic acid irritation in bladder capacity strongly indicates efficacy in the mammalian form of disorders of the lower urinary tract of painful and non-painful and associative and irritative symptoms in patients with normal and injured spinal cord. In addition, the combination of a modulator of the calcium channel subunit ot2d and a modulator of smooth muscle produces a synergistic effect that was greater than what would be expected if the effects were simply additive. Example 4 - Diluted Acetic Acid Model: Gabapentin and Tolterodin. Objective and Reasoned Exposure The objective of this study was to determine the ability of a calcium channel modulator subunit a__d in combination with a smooth muscle modulator to reverse the reduction in bladder capacity observed after continuous infusion of dilute acetic acid , a commonly used model of supra-active bladder. In particular, the current study used gabapentin as an exemplary calcium channel modulator o2d and tolterodine as an exemplary smooth muscle modulator.

Materials and Methods Normal female rats anesthetized with urethane (1.2 g / kg) were used in this study. Groups of rats were treated with tolterodine alone (n = 9), gabapentin only (n = ll) and 2 combination studies characterized by individual initial dose combinations of tolterodine (Medium and High) together with the low dose of gabapentin, followed in turn, by the Medium and High dose of gabapentin only (n = 4 and n = 3, respectively). Drugs and Preparation The drugs were dissolved in normal saline at 1, 3 and 10 mg / ml for tolterodine and 10, 30 and 100 mg / ml for gabapentin. In these studies, individual doses can often be referred to as Low, Medium and High. The combinations are referred to as 3 mg / kg of Tolt. The combination and 10 mg / kg of Tolt. The combination. The animals were dosed in injection volume = body weight in kg. In Vivo Model Acute Anesthetized Animal Preparation: Female rats (250-300 g of body weight) were anesthetized with urethane (1.2 g / kg) and a catheter filled with saline solution (PE-50) was inserted into the jugular vein for the administration of intravenous drug. Via a midline lower abdominal incision, a wide tip PE 50 catheter was inserted into the bladder dome for filling the bladder and recording the pressure. The abdominal cavity was moistened with saline and closed by covering it with a thin plastic sheet, in order to maintain access to the bladder for emptying purposes. Electrodes of fine silver or stainless steel wire were inserted into the external urethral sphincter (EUS) percutaneously for electromyography (EMG). Experimental Design: Saline was infused continuously at a rate of 0.055 ml / min via the bladder filling catheter for 60 minutes to obtain a baseline of low urinary tract activity (continuous cystometry; CMG). After the control period, a solution of acetic acid at 0.25% saline was infused into the bladder at the same flow rate to induce bladder irritation. After 30 minutes of the AA infusion, 3 vehicle injections were made in an interval in 20 minutes to determine the effects of the vehicle, if any. "Subsequently, increased doses of an active agent selected as a combination of agents, in half-log increments were administered intravenously at 30 minute intervals in order to build a cumulative dose-response relationship at the end of the saline cystometry period. of control, the third vehicle, and 20 minutes after each subsequent treatment, the infusion pump was stopped, the bladder was emptied by withdrawing the fluid via the infusion catheter and a single filling cystometrogram was performed at the same proportion of flow in order to determine changes in bladder capacity caused by the irritation protocol and subsequent intravenous drug administration. Data Analysis The bladder capacity data for each animal was normalized to "% Recovery from Irritation", and this index was used as the measure of effectiveness. Data from the experiments in which each of the drugs were administered alone were used to create theoretical populations of additive effects for each dose (low, medium and high), and these were compared using the one-sided t test (comparisons of individual doses) and by 2-way ANOVA (combined doses) for the current combination drug data. The averages and standard deviations of each of the "corresponding dose" responses of the individual treatment (low, medium and high) were added together to estimate the average and the standard deviation of the theoretical additive populations for which to compare the current data obtained. of the combination experiments. The population of theoretical additive effect N = (Nantimuscarinic + N subunit modulator a2d) ~ 1 • P <0.050 was considered significant. Only the rats that showed a 50-90% reduction in bladder capacity in the third vehicle measurement when compared to the pre-irritation saline control values were used for numerical analysis. Results and Conclusions The effect of cumulative increased doses of tolterodine (n = 9), gabapentin (n = ll) and the two combinations tested (for example, dose 1 for the combination was 30 mg / kg gabapentin and 3 mg / kg of tolterodine, n = 4 and 3 for 3 and 10 mg / kg tolterodine, respectively) on bladder capacity is depicted in Figure 9. Data are normalized to saline controls and are presented as Average ± SEM. The effect of cumulative increased doses of tolterodine (n = 9), gabapentin (n = ll). and the 2 corresponding combinations (for example, Dose 1 for the combination was 10 mg / kg gabapentin and 3 mg / kg tolterodine, n = 4 and 3, for 3 mg / kg and 10 mg / kg tolterodine, respectively) on the capacity of the bladder (normalized to% Recovery from Irritation) is represented in Figure 10. The data are presented as Average ± SEM. Note that the drug combination produced a greater effect than the additive for the 3 mg / kg of Tolt. Combination (P = 0.0099) and 10 mg / kg of Tolt. Combination (P = 0.0104).

The ability of a calcium channel modulator a2d subunit in combination with a smooth muscle modulator to produce a dramatic reversal in the reduction induced by acetic acid irritation in bladder capacity strongly indicates efficacy in mammalian forms of disorders of the urinary tract under painful and not painful and associative irritative symptoms in patients with normal and injured spinal cord. In addition, the combination of a calcium channel modulator a2d subunit and a smooth muscle modulator produced a synergistic effect that was greater than what would be expected if the effects were simply additive. Example 5 - Diluted Acetic Acid Model: pregabalin and Tolterodine. Objective and Reasoned Exposure The objective of this study was to determine the ability of a calcium channel modulator subunit a_.d in combination with a modulator of smooth muscle to reverse the reduction in bladder capacity observed after continuous infusion of acid diluted acetic acid, a commonly used model of supra-active bladder. In particular, the current study used pregabalin as an exemplary oc2d subunit calcium channel modulator and tolterodine as an exemplary smooth muscle modulator. Materials and Methods Normal female rats anesthetized with urethane (1.2 g / kg) were used in this study. Groups of rats were treated with tolterodine only (n = 9), pregabalinin only (n = 7) and respective corresponding dose combinations of tolterodine and pregabalin (n = 9). Drugs and Preparation The drugs were dissolved in normal saline at 1, 3 and 10 mg / ml for tolterodine and 10, 30 and 100 mg / ml for pregabalin. In these studies, individual doses and combinations can be subsequently referred to as Low, Medium and High. The animals were dosed in injection volume = body weight in kg. In Vivo Model Anesthetized Acute Preparation of Animals: Female rats (250-300 g of body weight) were anesthetized with urethane (1.2 g / kg) and a catheter filled with saline solution (PE-50) was inserted into the jugular vein for the administration of intravenous drug. Via a midline lower abdominal incision, a wide tip PE 50 catheter was inserted into the bladder dome for filling the bladder and recording the pressure. The abdominal cavity was moistened with saline and closed by covering it with a thin plastic sheet, in order to maintain access to the bladder for emptying purposes. Electrodes of fine silver or stainless steel wire were inserted into the external urethral sphincter (EUS) percutaneously for electromyography (EMG). Experimental Design: Saline was infused continuously at a rate of 0.055 ml / min via the bladder filling catheter for 60 minutes to obtain a baseline of low urinary tract activity (continuous cystometry; CMG). After the control period, a solution of 0.25% acetic acid saline was infused into the bladder at the same flow rate to induce irritation. bladder. After 30 minutes of AA infusion, 3 vehicle injections were made in a 20 minute interval to determine the effects of the vehicle, if any. Subsequently, increased doses of a selected active agent, as a combination of agents, in half log increments were administered intravenously at 30 minute intervals in order to build a cumulative dose-response relationship. At the end of the control saline cistometry period, the third vehicle, and 20 minutes after each subsequent treatment, the infusion pump was stopped, the bladder was emptied by withdrawing the fluid via the infusion catheter and a Single filling cystometrogram was performed at the same flow rate in order to determine changes in bladder capacity caused by the irritation protocol and subsequent intravenous drug administration.

Data Analysis The bladder capacity data for each animal was normalized to "% Recovery from Irritation", and this index was used as the measure of effectiveness. Data from the experiments in which each of the drugs were administered were used only to create theoretical populations of additive effects for each dose (low, medium and high), and these were compared using the one-sided t test (comparisons of individual doses) and by 2-way ANOVA (combined doses) to the current combination drug data. The averages and standard deviations of each of the "corresponding dose" responses of the individual treatment (low, medium and high) were added together to estimate the average and the standard deviation of the theoretical additive populations for which to compare the current data. obtained from the combination experiments. The population of theoretical additive effects N = (Nantimuscarinic + N subunit modulator or? 2d) -l-P < 0 050 S? considered significant. Only rats that showed a 50-90% reduction in bladder capacity in the measurement of the third vehicle when compared to the pre-irritation saline control values were used for numerical analysis. Results and Conclusions The effect of cumulative increased doses of tolterodine (n = 9), pregabalin (n = 7) and their corresponding combinations (eg, Dose 1 for the combination was 10 mg / kg pregabalin and 1 mg / tolterodin kg, n = 9) on the capacity of the bladder is represented in Figure 11. The data are normalized to the saline controls and are presented as Mean ± SEM. The effect of cumulative increased doses of tolterodine (n = 9), pregabalin (n = 7) and corresponding combinations (eg, Dose 1 for the combination was 10 mg / kg pregabalin and 1 mg / kg tolterodine; n = 9) on the capacity of the bladder (normalized to% Recovery from Irritation) is represented in Figure 12. The data are presented as Average ± SEM. Note also that the combination of drugs produced a greater effect than the additive in the Median doses (P = 0.0353) on the reduction and capacity of the bladder caused by the continuous intravesical exposure of diluted acetic acid. The synergy is also suggested by significant differences between the additive and combination effects by 2-way ANOVA. (P = 0.0234). The ability of a calcium channel modulator a2d subunit in combination with a smooth muscle modulator to produce a dramatic reversal in the reduction induced by acetic acid irritation in bladder capacity strongly indicates efficacy in mammalian forms of painful and non-painful urinary tract disorders and associative irritative symptoms in patients with normal and injured spinal cord. In addition, the combination of a calcium channel modulator a2d subunit and a smooth muscle modulator produced a synergistic effect that was greater than what would be expected if the effects were simply additive. Example 6 - Diluted Acetic Acid Model: Gabapentin and Propiverin. Objective and Reasoned Exposure The objective of this study was to determine the ability of a calcium channel modulator a2d subunit in combination with a smooth muscle modulator to reverse the reduction in bladder capacity observed after continuous infusion of dilute acetic acid , a commonly used model of supra-active bladder. In particular, the current study used gabapentin as an exemplary a2d subunit calcium channel modulator and propiverine as an exemplary smooth muscle modulator. Materials and Methods Normal female rats anesthetized with urethane (1.2 g / kg) were used in this study. Groups of rats were treated with propiverine only (n = 7), gabapentin only (n = ll) and respective corresponding dose combinations of propiverine and gabapentin (n = 10).

Drugs and Preparation Drugs were dissolved in normal saline at 3, 10 and 30 mg / ml for propiverine and 10, 30 and 100 mg / ml for gabapentin. In these studies, individual doses and combinations can subsequently be referred to as Low, Medium and High. The animals were dosed in injection volume = body weight in kg. In vivo Model Acute Anesthetized Animal Preparation: Female rats (250-300 g of body weight) were anesthetized with urethane (1.2 g / kg) and a catheter filled with saline (PE-50) was inserted into the jugular vein for intravenous drug administration. Via a midline lower abdominal incision, a wide tip PE 50 catheter was inserted into the bladder dome for filling the bladder and recording the pressure. The abdominal cavity was moistened with saline and closed by covering it with a thin plastic sheet, in order to maintain access to the bladder for emptying purposes. Electrodes of fine silver or stainless steel wire were inserted into the external urethral sphincter (EUS) percutaneously for electromyography (EMG). Experimental Design: Saline was infused continuously at a rate of 0.055 ml / min via the bladder filling catheter for 60 minutes to obtain a baseline of low urinary tract activity (continuous cystometry; CMG). After the control period, a solution of 0.25% acetic acid in saline was infused into the bladder at the same flow rate to induce bladder irritation. After 30 minutes of the AA infusion, 3 vehicle injections were made at 20 minute intervals to determine the effects of the vehicle, if any. Subsequently, increased doses of a selected active agent, or combination of agents, in half log increments were administered intravenously at 30 minute intervals in order to build a cumulative dose-response relationship. At the end of the control saline cistometry period, the third vehicle, and 20 minutes after each subsequent treatment, the infusion pump was stopped, the bladder was emptied by withdrawing the fluid via the infusion catheter and a Single filling cystometrogram was performed at the same flow rate in order to determine changes in bladder capacity caused by the irritation protocol and subsequent intravenous drug administration. Data Analysis Bladder capacity data for each animal was normalized to "% Control Irritation", and this index was used as the measure of efficacy. The data from the experiments in which each of the drugs were administered were only used to create theoretical populations of additive effects for each dose (low, medium and high), and these were compared using a one-sided t test (comparisons of individual doses) and by 2-Way ANOVA (combined doses) for the current combination drug data. The averages and standard deviations of each of the "combined dose" responses of the individual treatment (low, medium and high) were added together to estimate the average and standard deviation of the theoretical additive populations for which they are compared with the current data obtained from the combination experiments. The population of theoretical additive effect N-. Nantimuscarinic "*" N subunit modulator a2ó) - 1. P < 0.050 was considered significant. Only rats that showed a 50-90% reduction in bladder capacity in the third measurement of the vehicle when compared with pre-irritation saline control values were used for numerical analysis. Results and Conclusions The effect of cumulative increased doses of propiverine (n = 7), recorpentin (n = ll) and their corresponding combinations (eg, Dose 1 for the combination was 10 mg / kg gabapentin and 3 mg / kg propiverina; n = 10) on the capacity of the bladder is represented in Figure 13. The data are normalized to saline controls and are represented as Mean ± SEM. The effect of cumulative increased doses of propiverine (n = 7), gabapentin (n = ll) and their corresponding combinations (eg, Dose 1 for the combination was 10 mg / kg gabapentin and 3 mg / kg propiverine; n = 10) on the capacity of the bladder (normalized to% Recovery from Irritation) is represented in Figure 14. The data is presented as Average ± SEM. Note that the combination of drugs produced a greater effect than the additive of the Low (P = 0.0087) and Medium (P = 0.0253) doses in the reduction of bladder capacity caused by continuous intravesical exposure to dilute acetic acid. Synergy is also suggested by significant differences between the additive effects and the 2-way ANOVA combination (P = 0.0067). The ability of a modulator of the calcium channel subunit oc2d in combination with a smooth muscle modulator to produce a dramatic reversal in the reduction induced by acetic acid irritation in bladder capacity strongly indicates efficacy in the mammalian forms of painful and non-painful urinary tract disorders and associated irritative symptoms in patients with normal and injured spinal cord. In addition, the combination of a calcium channel modulator a2d subunit and a smooth muscle modulator produced a synergistic effect that was greater than what would be expected if the effects were simply additive. Example 7 - Diluted Acetic Acid Model: Gabapentin and Solifenacin Objective and Reasoned Exposure The objective of this study was to determine the ability of a calcium channel modulator subunit a_.d in combination with a modulator of smooth muscle to reverse the reduction in the bladder capacity observed after continuous infusion of diluted acetic acid, a commonly used model of supra-active bladder. In particular, the current study used gabapentin as an exemplary a2d subunit calcium channel modulator and solifenacin as an exemplary smooth muscle modulator. Materials and Methods Normal female rats anesthetized with urethane (1.2 g / kg) were used in this study. Groups of rats were treated with solifenacin only (n = 7), gabapentin only (n = ll) and respective corresponding dose combinations of solifenacin and gabapentin (n = 10). Drugs and Preparation The drugs were dissolved in normal saline at 1, 3 and 10 mg / ml for solifenacin and 10, 30 and 100 mg / ml for gabapentin. In these studies, individual doses and combinations can be subsequently referred to as Low, Medium and High. The animals were dosed in injection volume = (body weight in kg) * 1.5. In vivo Model Anesthetized Acute Preparation of Animals: Female rats (250-300 g of body weight) were anesthetized with urethane (1.2 g / kg) and a catheter filled with saline (PE-50) was inserted into the jugular vein for the administration of intravenous drug. Via a midline lower abdominal incision, a wide tip PE 50 catheter was inserted into the bladder dome for filling the bladder and recording the pressure. The abdominal cavity was moistened with saline solution and closed by covering with a thin sheet of plastic, in order to maintain access to the bladder for emptying purposes. Electrodes of fine silver or stainless steel wire were inserted into the external urethral sphincter (EUS) percutaneously for electromyography (EMG). Experimental Design: Saline was infused continuously at a rate of 0.055 ml / min via the bladder filling catheter for 60 minutes to obtain a baseline of low urinary tract activity (continuous cystometry; CMG). After the control period, a solution of 0.25% acetic acid saline was infused into the bladder at the same flow rate to induce bladder irritation. After 30 minutes of the AA infusion, 3 vehicle injections were made at 20 minute intervals to determine the effects of the vehicle, if any. Subsequently, increased doses of a selected active agent, or combination of agents, in half log increments were administered intravenously at 30 minute intervals in order to build a cumulative dose-response relationship. At the end of the control saline cistometry period, the third vehicle, and 20 minutes after each subsequent treatment, the infusion pump was stopped, the bladder was emptied by withdrawing the fluid via the infusion catheter and a single filling cystometrogram was performed at the same proportion of flow in order to determine changes in bladder capacity caused by the irritation protocol and subsequent intravenous drug administration. Data Analysis The bladder capacity data for each animal was normalized to "% Recovery from Irritation", and this index was used as the measure of effectiveness. Data from the experiments in which each of the drugs were administered were only used to create theoretical populations of additive effects for each dose (low, medium and high), and these were compared using the one-sided t test (comparisons of individual doses) and by 2-way ANOVA (combined doses) to the current combination drug data. The averages and standard deviations of each of the "corresponding dose" responses of the individual treatment (low, medium and high) were added together to estimate the average and standard deviation of the theoretical additive populations for which to compare the current data obtained of the combination experiments. The population of theoretical additive effects S N = (Nantimuscarinic + N subunit modulator a2d) ~ l. P <; 0 050 S? considered significant. Only rats that showed a 50-90% reduction in bladder capacity in the third measurement of the vehicle when compared with pre-irritation saline control values were used for numerical analysis. Results and Conclusions The effect of the cumulative increased doses of solifenacin (n = 4), grabapentin (n = ll) and their corresponding combinations (for example, the dose 1 for the combination was 10 mg / kg gabapentin and 3 mg / kg of solifenacin, n = 12) on the capacity of the bladder is represented in Figure 15. The data are normalized to the saline controls and are presented as Mean ± SEM. The effect of cumulative increased doses of solifenacin (n = 4), gabapentin (n = ll) and their corresponding combinations (eg, Dose 1 for the combination was 10 mg / kg gabapentin and 3 mg / kg solifenacin; n = 12) on the capacity of the bladder (normalized to% Irritation Control) is represented in Figure 16. The data are presented as Average ± SEM. Note that the combination of drugs produced a greater effect than the additive in the Low (P <0.05) and High (P <0.05) doses on the reduction in bladder capacity caused by continuous intravesical exposure to dilute acetic acid . The synergy is also suggested by significant differences between the additive and combination effects for 2-way ANOVA (P <0.0022). The ability of a calcium channel modulator a? D subunit in combination with a smooth muscle modulator to produce a dramatic reversal in the reduction induced by acetic acid irritation in bladder capacity strongly indicates efficacy in mammalian forms of painful and non-painful urinary tract disorders and associated irritative symptoms in patients with normal and injured spinal cord. In addition, the combination of a calcium channel modulator subunit or > d and a smooth muscle modulator produced a synergistic effect that would be greater than what would be expected if the effects were simply additive. Example 8 - Diluted Acetic Acid Model in Cats: Gabapentin and Oxybutynin Objective and Reasoned Exposure The objective of this study was to determine the ability of a calcium channel modulator a2d subunit in combination with a smooth muscle modulator to reverse the reduction in the bladder capacity observed after continuous infusion of diluted acetic acid, in a cat model, a commonly used model of supra-active bladder. In particular, the current study used gabapentin as a modulator of the calcium channel subunit cd exemplary and oxybutynin as an exemplary smooth muscle modulator. Materials and Methods Normal female cats (2.5-3.5 kg; Harian) anesthetized with alpha-chloralose (50-100 mg / kg) were used in this study. Groups of cats were treated with oxybutynin alone (n = 5), gabapentin only (n = 5) and combinations of corresponding doses selected from oxybutynin and gabapentin (n = 6). Drugs and Preparation The drugs were dissolved in saline in 0. 01, 0.03, 0.3, 1.0, 3.0 and 10 mg / ml for oxybutynin and 3.0, 10, 30, 100 and 300 mg / ml for gabapentin. The combinations corresponded to 0.1 mg / kg of oxybutynin and 3 mg / kg of gabapentin (Low), 0.03 mg / kg of oxybutynin and 10 mg / kg of gabapentin (Medium, and 1.0 mg / kg of oxybutynin and 30 mg / kg of gabapentin (High) The animals were dosed in an injection volume = body weight in kg Model In Vivo Anesthetized Acute Female cats (2.5-3.5 kg; Harían) had their food removed at night before the experiment. Tomorrow the cat was anesthetized with isoflurane and prepared for surgery using the septic technique Polyethylene catheters were genetically placed to allow measurement of bladder pressure, urethral pressure, blood pressure, respiratory rate as well as for Drug delivery Fine wire electrodes were implanted along the external urethral anal sphincter After the surgery, the cats were slowly changed from the anesthetic gas isoflurane (2-3.5%) to alpha-chloralose (50-100 mg / kg ) . During At control cystometry, saline was infused slowly into the bladder (0.5-1.0 ml / min) for 1 hour. The control cystometry was followed by 0.5% acetic acid in saline for the duration of the experiment. After estimating the cystometric variables under these baseline conditions, the effects of the test drug (s) on micturition was determined by the 3-5-point dose-response protocols. Data Analysis For the purposes used in the synergy using all the data simultaneously, the bladder capacity data for each animal was normalized to% Recovery from Irritation, and this index was used as the measure of effectiveness. The data from the experiments in which each of the drugs were administered were only used to create theoretical populations of the additive effects for each dose (low, medium and high), and these were compared using the one-sided t test ( individual dose comparisons) and by 2-Way ANOVA (combined doses) to the current combination drug data. For these purposes, the averages and standard deviations of each of the "corresponding dose" responses of the individual worker (low, medium and high) were added together to estimate the average and standard deviation of the theoretical additive populations for which to compare the current data obtained from the combination experiments. THE THEORETICAL ADDICTION EFFECTS N = (Nantimuscarinic + Modulator subunit a2d) ~ 1. Because gabapentin alone was not tested at doses of 3.0 and 10.0 mg / kg, and because there were no significant effects for gabapentin at the 30 mg / kg dose alone, the 30 mg / kg response was used as a substitute for the response of 3.0 and 10.0 mg / kg in order to calculate the theoretical additive population. P < 0.050 was considered significant. Additionally, the% of Evacuation Efficiency was determined by the following formula: (Evacuated Volume / (Evacuated + Residual Volume)) * 100 for oxybutynin alone, gabapentin only and the combination. Results and Conclusions The effects of cumulative increased doses of oxybutynin (n = 5), recorpentin (n = 5) and their corresponding combinations (n = 6) on bladder capacity are represented in Figure 17. Data are normalized to saline controls and are presented as mean ± SEM. The theoretical additive effect of cumulative increased doses of oxybutynin (n = 5) and gabapentin (n = 5) and their corresponding combinations (for example, the Dose 1 for the combination was 3 mg / kg of gabapentin and 0. 1 mg / kg oxybutynin; n = 6) on the capacity of the bladder (Normalized to% Recovery from Irritation) is represented in Figure 18. The data is presented as Average ± SEM. Note that the combination of drugs produced a greater effect than the additive in the Medium dose (P == 0.0490) on the reduction in bladder capacity caused by continuous intravesical exposure to dilute acetic acid. The effect of cumulative increased doses of oxybutynin (n = 5, gabapentin (n = 5) on evacuation efficiency is depicted in Figure 19 (oxybutynin in Figure 19A, gabapentin in Figure 19B). the dose of evacuation efficiency caused by oxybutynin.Also note that gabapentin had no effect.The effect of cumulative increased doses of oxybutynin and gabapentin in combinations (n = 6) on evacuation efficiency is shown in Figure 20. Note that the dose-dependent decrease and evacuation efficiency caused by oxybutynin is virtually prevented by the co-administration of gabapentin.In the combination of higher dose of oxybutynin (1 mg / kg) and gabapentin (30 mg / kg) tested in the cat, evacuation efficiency was decreased by only 16.7%. This is a sharp contrast to the effect of oxybutynin only in the same doses, which resulted in a 78.4% decrease in evacuation efficiency. It was concluded that the addition of gabapentin (which alone in this dose caused a 10.1% increase in evacuation efficiency) counteracts the negative and desirable effects of oxybutynin on evacuation efficiency while simultaneously providing a desirable positive synergistic effect on capacity of the increased bladder. The ability of a calcium channel modulator a2d subunit in combination with a smooth muscle modulator to produce a dramatic reversal in the reduction induced by acetic acid irritation in the bladder capacity strongly indicates efficacy in the mammalian forms of urinary tract disorders under painful and non-painful and associative irritative symptoms in patients with normal and injured spinal cord. In addition, the combination of a modulator of the calcium channel subunit a2d and a modulator of smooth muscle produced a synergistic effect that was greater than what would be expected if the effects were simply additive. In addition, the ability of a calcium channel modulator a2d subunit to counteract the negative side effects of a smooth muscle modulator while simultaneously producing a positive synergistic effect on the bladder's supractivity strongly suggests efficacy in relieving irritative symptoms without compromising the ability to evacuate obstructed patients leaving the bladder, such as those suffering from benign prostatic hyperplasia and associated irritative symptoms. Example 9 - Spinal Cord Injury Model: Gabapentin and Oxybutynin Objective and Reasoned Exposure The objective of this study was to determine the ability of the calcium channel modulator a2ó subunit in combination with a smooth muscle modulator on the ability to increase the capacity of the bladder in rats injured in the spinal cord (SCI), a commonly used model of neurogenic bladder. In particular, the current study used gabapentin as an exemplary calcium channel modulator o2d and oxybutynin as an exemplary smooth muscle modulator. Materials and Methods SCI female rats with restricted awakening were treated with combinations of oxybutynin and gabapentin (n = 3). Cumulative dose-response protocols were used with mean log increments for all studies. Drugs and Preparations The drugs were dissolved in normal saline at 1, 3 and 10 mg / ml for oxybutynin and 30, 100 and 300 mg / ml for gabapentin. In these studies, the combinations can be subsequently referred to as Low, Medium and High. In Vivo SCI Model of Restricted Awakening Animal Preparation: Female rats (250-300 g of body weight) were anesthetized with 4% isoflurane (2% maintenance) and a laminectomy was performed at the spinal level T9-10. The spinal cord completely transected, and the wound was closed in layers. The animals received antibiotic (100 mg / kg of ampicillin) immediately and every third day during recovery until the day of terminal experimentation. The SCI rats had their bladders manually expressed twice a day, by external crede, and were kept in a single housing for 2-3 weeks until evidence of recovery of the evacuation function was observed. On the day of the experiment, the animals were anesthetized with 4% isoflurane (2% maintenance) and a catheter filled with saline (PE-50) was inserted into the jugular vein for intravenous drug administration. This catheter was removed through the idscapular region and the ventral wound closed with silk. Via a midline lower abdominal incision, a wide tip PE 50 catheter was inserted into the bladder dome for filling the bladder and recording the pressure. The abdominal cavity was closed in layers, with the bladder catheter coming out at the apex of the wound. Electrodes of fine silver or stainless steel wire were inserted into the external urethral sphincter (EUS) percutaneously for electromyography (EMG). The animal was placed in a Ballman restriction cage and allowed to recover from anesthesia for 1 hour before the collection of control data. Experimental design: Saline was infused continuously at a rate of 0.100 ml / min via the bladder filling catheter for 60 minutes to obtain a baseline of low urinary tract activity (continuous cystometry; CMG). After the control period, 3 vehicle injections were made at 20 minute intervals to determine the effects of the vehicle, if any. Subsequently, increased doses of a selected active agent, or combination of agents, in half log increments were administered intravenously at 30 minute intervals in order to build a cumulative dose-response relationship. At the end of the control cystometry period, the third vehicle (Veh 3), and 20 minutes after each subsequent treatment, the infusion pump was stopped, the bladder was emptied by withdrawing the fluid via the infusion catheter and A single filling cystometrogram was performed at the same flow rate in order to determine changes in bladder capacity, as determined by an evacuation contraction, caused by intravenous drug administration. Data Analysis The bladder capacity data for each animal was normalized to% of Veh 3, and the data were analyzed using an I-Way ANOVA of nonparametric repeated measurements (Friedman Test) with the Post- Dunn's Multiple Comparison test. The P < 0.05 was considered significant. Results and Conclusions The effect of cumulative increased doses of the combination of oxybutynin and gabapentin (for example, Dosage 1 for the combination was 30 mg / kg gabapentin and 1 mg / kg oxybutynin, n = 3) on the capacity of the bladder in chronic SCI rats is represented in Figure 21. Observe the dose-dependent increase in the remarkable capacity of the bladder (P = 0.0278). The data is normalized to vehicle controls and is presented as Media + SEM. The effect of increased and cumulative doses of the combination of oxybutynin and gabapentin (n = 3) on the instability of the bladder, as measured by a significant decrease in the number of non evacuation contractions greater than 8 cm of H0 (P = 0.0174), is represented in Figure 22. The data is presented as Media + SEM. The effect of increased and cumulative doses of the combination of oxybutynin and gabapentin (n = 3) on the instability of the bladder, as measured by a significant decrease in latency for the occurrence of non-evacuation contractions (P = 0.017), it is represented in Figure 23. The data is presented as Media + SEM. The combination of a modulator of the calcium channel subunit a2d and the smooth muscle modulator was able to almost double bladder capacity and significantly reduce bladder instability in a neurogenic bladder rat model. This discovery is established in contrast to the effects of vanilloid agents, such as capsaicin, which have been shown to reduce bladder instability in SCI rats, but do not affect the ability of the bladder to evacuate (Cheng et al., 1995). , Brain Res. 678: 40-48). Because both spinal cord injury and benign protractive hyperplasia are characterized by exit obstruction, bladder hypertrophy, and bladder instability, these findings strongly indicate efficacy for both marrow injury spinal as benign protative hyperplasia, including irritative symptoms and / or obstructive symptoms associated with benign prostatic hyperplasia. All publications and patent applications mentioned in the specification are indicative of the level of those skilled in the art to which this invention pertains. All publications and patent applications are incorporated herein by reference to the same extent as if each individual patent application or publication was specifically and individually indicated to be incorporated by reference.

Claims (72)

1. CLAIMS 1. A method for treating a disorder of the ordinary lower tract characterized by having at least one symptom, selected from the group consisting of urinary frequency, urinary urgency and nocturia, characterized in that it comprises administering to an individual 'in need thereof. a therapeutically effective amount of a calcium channel modulator 2d subunit in combination with a smooth muscle modulator, wherein the smooth muscle modulator is selected from the group consisting of an antimuscarinic, an adrenergic agonist / 33, a spasmolytic, an antagonist Neurokinin receptor, a receptor antagonist of bradykinin and a nitric oxide donor.
2. 2. The method according to claim 1, characterized in that the modulator of the calcium channel subunit a2d and the modulator of the smooth muscle are contained within a single pharmaceutical formation.
3. 3. The method according to claim 1, characterized in that the modulator of the calcium channel subunit a2d and the smooth muscle modulator are contained within separate pharmaceutical formations.
4. 4. The method according to claim 3, characterized in that the calcium channel modulator subunit a and the smooth muscle modulator are administered concurrently.
5. 5. The method according to claim 3, characterized in that the modulator of the calcium channel subunit 2d and the smooth muscle modulator are administered sequentially.
6. 6. The method of compliance with the claim 1, characterized in that the modulator of the calcium channel subunit a2d is a GABA analogue.
7. The method according to claim 6, characterized in that the GABA analog is Gabapentin or an acid, salt, enantiomer, analog, ester, amide, prodrug, active metabolite or derivative thereof.
8. The method according to claim 6, characterized in that the GABA analog is Pregabalin or an acid, salt, enantiomer, analog, ester, amide, prodrug, active metabolite or derivative thereof.
9. 9. The method according to claim 1, characterized in that the smooth muscle modulator is an antimuscarinic.
10. The method according to claim 9, characterized in that the antimuscarinic agent is oxybutynin or an acid, salt, enantiomer, analog, ester, amide, prodrug, active metabolite or derivative thereof.
11. The method according to claim 9, characterized in that the antimuscarinic agent is Tolterodine or an acid, salt, enantiomer, analog, ester, amide, prodrug, active metabolite or derivative thereof.
12. The method according to claim 9, characterized in that the antimuscarinic agent is Propiverine or an acid, salt, enantiomer, analog, ester, amide, prodrug, active metabolite or derivative thereof.
13. The method according to claim 9, characterized in that the antimuscarinic acid is Solifenacin monohydrochloride or an acid, salt, enantiomer, analogue, ester, amide, prodrug, active metabolite or derivative thereof.
14. 14. The method according to the claim 1, characterized in that the modulator of the calcium channel subunit a2d is Gabapentin or acids, salts, enantiomers, analogues, esters, amides, prodrugs, active metabolites or derivatives thereof, and wherein the modulator of the smooth muscle is oxybutynin or acids, salts , enantiomers, analogues, esters, amides, prodrugs, active metabolites or derivatives thereof.
15. The method according to claim 1, characterized in that the modulator of the calcium channel subunit a2d is Pregabalin or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites or derivatives thereof, and wherein the modulator of the smooth muscle is oxybutynin or acids, salts, enantiomers, analogues, esters, amides, prodrugs, active metabolites and derivatives thereof.
16. 16. The method according to claim 1, characterized in that the modulator of the calcium channel subunit a2d and the smooth muscle modulator are administered on a base as necessary.
17. 17. The method of compliance with the claim 1, characterized in that the modulator of the calcium channel subunit a2d and the modulator of the smooth muscle are administered before the start of an activity where the suppression of the symptoms of a low urinary tract disorder would be desirable.
18. 18. The method according to claim 17, characterized in that the modulator of the calcium channel modulator a2d subunit and a smooth muscle modulator are administered from about 0 to about 3 hours before the start of an activity where it would be desirable to suppress the symptom.
19. The method according to claim 1, characterized in that the modulator of the calcium channel subunit a2d and the smooth muscle modulator are administered orally, transmucosally, sublingually, buccally, intranasally, transurethrally, rectally, by inhalation, topically, transdermally, parenterally, intrathecally, vaginally or perivaginally.
20. The method according to claim 1, characterized in that the modulator of the calcium channel subunit a2d and the smooth muscle modulator are administered to treat the supra-active bladder or the irritative or obstructive symptoms of benign prostatic hyperplasia.
21. The method according to claim 1, characterized in that the modulator of the calcium channel subunit a2d and the smooth muscle modulator are administered to treat the urinary frequency.
22. The method according to claim 1, characterized in that the modulator of the calcium channel subunit a2d and the smooth muscle modulator are administered to treat urinary urgency.
23. 23. The method according to claim 1, characterized in that the modulator of the calcium channel subunit a2d and the smooth muscle modulator are administered to treat nocturia.
24. The method according to claim 1, characterized in that at least one deleterious side effect associated with the individual administration of the calcium channel modulator subunit a2d or the individual administration of the smooth muscle modulator is diminished by the concurrent administration of the modulator of the calcium channel subunit a2d and the smooth muscle modulator.
25. 25. The method according to claim 24, characterized in that the modulator of the calcium channel subunit a2d and the smooth muscle modulator are administered to treat the supra-active bladder or the irritative or obstructive symptoms of the benign protative hyperplasia.
26. 26. The method for treating a disorder of the lower urinary tract characterized by having at least one symptom selected from the group consisting of urinary frequency, urinary urgency and nocturia, characterized in that it comprises administering to an individual in need thereof, an amount Therapeutically effective of at least one component selected from a calcium channel modulator a2d subunit and a smooth muscle modulator, wherein the smooth muscle modulator is selected from the group consisting of an antimuscarinic, a β3 adrenergic agonist, a spasmolytic, a receptor antagonist of neurokinin, a receptor antagonist of bradykinin and a nitric oxide donor.
27. 27. A method for treating a symptom of a lower urinary tract disorder, characterized in that it comprises: (a) administering a calcium channel modulator subunit a2d selected from the group consisting of Gabapentin and Pregabalin; and (b) administering an antimuscarinic selected from the group consisting of Oxybutynin, Tolterodine, Propiverine and Solifenacin monohydrochloride; wherein the modulator of the calcium channel subunit 2d and the antimuscarinic are in therapeutically effective amounts sufficient to treat a symptom of a low urinary tract disorder.
28. 28. The method according to claim 27, characterized in that the symptom of a low urinary tract disorder is the urinary frequency.
29. 29. The method according to claim 27, characterized in that the symptom of a low urinary tract disorder is urinary urgency.
30. 30. The method of compliance with the claim 27, characterized in that the symptom of a low urinary tract disorder is nocturia.
31. 31. The method according to claim 27, characterized in that the symptom of a low urinary tract disorder is incontinence.
32. The method according to claim 27, characterized in that at least one deleterious side effect associated with the individual administration of the calcium channel modulator 2d subunit or the individual administration of the smooth muscle modulator is diminished by the concurrent administration of the modulator of the channel calcium subunit a2d and the antimuscarinic.
33. 33. The method according to claim 27, characterized in that the modulator of the calcium channel subunit a2d is Gabapentin and wherein the antimuscarinic agent is Oxybutynin.
34. 34. The method according to claim 27, characterized in that the modulator of the calcium channel subunit 2d is Gabapentin and wherein the antimuscarinic is Tolterodine.
35. 35. The method according to claim 27, characterized in that the modulator of the calcium channel subunit a2d is Gabapentin and wherein the antimuscarinic agent is Propiverine.
36. 36. The method of compliance with the claim 27, characterized in that the modulator of the calcium channel subunit a2d is Gabapentin and wherein the antimuscarinic is Solifenacin monohydrochloride.
37. 37. The method according to claim 27, characterized in that the modulator of the calcium channel subunit a d is Pregabalin and wherein the antimuscarinic is Oxybutynin.
38. 38. The method according to claim 27, characterized in that the modulator of the calcium channel subunit a2d is Pregabalin and wherein the antimuscarinic is Tolterodine.
39. 39. The method according to claim 27, characterized in that the modulator of the calcium channel subunit a2d is Pregabalin and wherein the antimuscarinic is Propiverine.
40. 40. The method according to claim 27, characterized in that the modulator of the calcium channel subunit 2d is Pregabalin and wherein the antimuscarinic is Solifenacin monohydrochloride.
41. 41. A pharmaceutical composition, characterized in that it comprises a modulator of the calcium channel subunit a2d which is a modulator of the calcium channel subunit a_d in combination with a modulator of smooth muscle, wherein the modulator of the calcium channel subunit a2d and the modulator of the smooth muscle are in sufficient amounts to treat a low urinary tract disorder characterized by having at least one symptom selected from the group consisting of urinary frequency, urgency and nocturia, and wherein the smooth muscle modulator is selected from the group which consists of an antimuscarinic, a β3 adrenergic agonist, and a bradiquinin receptor antagonist.
42. 42. A pharmaceutical composition, characterized in that it comprises: (a) a calcium channel modulator a2d subunit selected from the group consisting of Gabapentin and Pregabalin; and (b) an antimuscarinic selected from the group consisting of Oxybutynin, Tolterodine, Propiverine and Solifenacin monohydrochloride; wherein the modulator of the calcium channel subunit ad and the antimuscarinic are in therapeutically effective amounts sufficient to treat a symptom of a lower urinary tract disorder characterized by having at least one symptom selected from the group consisting of urinary frequency, urinary urgency and nocturia.
43. 43. The pharmaceutical composition according to claim 42, characterized in that the modulator of the calcium channel subunit a2d is present in an amount of about 50 mg to about 2400 mg, and wherein the antimuscarinic is present in an amount equal to or less than that approximately 5 mg.
44. 44. The pharmaceutical composition according to claim 43, characterized in that the calcium channel modulator subunit 2d is in an amount of about 200 mg.
45. 45. The pharmaceutical composition, according to claim 42, characterized in that the antimuscarinic is in an amount of about 2.5 mg.
46. 46. The pharmaceutical composition, according to claim 42, characterized in that the antimuscarinic is in an amount of about 1.25 mg.
47. 47. The pharmaceutical composition according to claim 42, characterized in that the modulator of the calcium channel subunit a2d and the antimuscarinic are formulated for oral, transmucosal, sublingual, buccal, intranasal, transurethral, rectal, inhalation, topical, transdermal, parenteral administration , intrathecal, vaginal or perivaginal.
48. 48. The pharmaceutical composition according to claim 42, characterized in that the symptom of a low urinary tract disorder is associated with benign protative hyperplasia or supra-active bladder.
49. 49. The pharmaceutical composition according to claim 42, characterized in that the symptom of a low urinary tract disorder is the urinary frequency.
50. 50. The pharmaceutical composition according to claim 42, characterized in that the symptom of a low urinary tract disorder is urinary urgency.
51. 51. The pharmaceutical composition according to claim 42, characterized in that the symptom of a low urinary tract disorder is nocturia.
52. 52. The pharmaceutical composition according to claim 42, characterized in that the symptom of a low urinary tract disorder is incontinence.
53. 53. The pharmaceutical composition according to claim 42, characterized in that the calcium channel modulator subunit 2d is Gabapentin and wherein the antimuscarinic is Oxybutynin.
54. 54. The pharmaceutical composition according to claim 42, characterized in that the modulator of the calcium channel subunit to d is Pregabalin and wherein the antimuscarinic is Oxybutynin.
55. 55. The pharmaceutical composition according to claim 42, characterized in that the modulator of the calcium channel subunit a2d is Gabapentin and wherein the antimuscarinic is Tolterodine.
56. 56. The pharmaceutical composition according to claim 42, characterized in that the modulator of the calcium channel subunit a2d is Gabapentin and wherein the antimuscarinic is Propiverine.
57. 57. The pharmaceutical composition according to claim 42, characterized in that the modulator of the calcium channel subunit to d is Gabapentin and wherein the antimuscarinic is Solifenacin monohydrochloride.
58. 58. The pharmaceutical composition according to claim 42, characterized in that the modulator of the calcium channel subunit a2d is Pregabalin and wherein the antimuscarinic is Oxybutynin.
59. 59. The pharmaceutical composition according to claim 42, characterized in that the modulator of the calcium channel subunit 2d is Pregabalin and wherein the antimuscarinic is Tolterodine.
60. 60. The pharmaceutical composition according to claim 42, characterized in that the modulator of the calcium channel subunit a2d is Pregabalin and wherein the antimuscarinic is Propiverine.
61. 61. The pharmaceutical composition according to claim 42, characterized in that the modulator of the calcium channel subunit 2d is Pregabalin and wherein the antimuscarinic is Solifenacin monohydrochloride.
62. 62. The pharmaceutical composition according to claim 42, characterized in that the modulator of the calcium channel subunit a.and the antimuscarinic are present in a ratio of approximately 1: 1 to approximately 800: 1 or approximately 1: 1 to approximately 1. : 800, respectively, based on a fraction of their respective ED50 values.
63. 63. The pharmaceutical composition according to claim 62, characterized in that the modulator of the calcium channel subunit 2d is Gabapentin and the antimuscarinic is Oxybutynin.
64. 64. The pharmaceutical composition according to claim 42, characterized in that the modulator of the calcium channel subunit a2d and the antimuscarinic are present in a weight / weight ratio of 1: 1 to approximately 800: 1 or from approximately 1: 1 to approximately 1: 800, respectively.
65. 65. The pharmaceutical composition according to claim 64, characterized in that the modulator of the calcium channel subunit 2d is Gabapentin and the antimuscarinic agent is Oxybutynin.
66. 66. A kit packaged for a patient for use in a treatment of a disorder in the lower urinary tract characterized by having at least one symptom selected from the group consisting of urinary frequency, urinary urgency and nocturia, characterized in that it comprises: (a) a calcium channel modulator 2d subunit; (b) a smooth muscle modulator, selected from the group consisting of an antimuscarinic, an adrenergic agonist / 33 and a bradykinin receptor antagonist; (c) a container containing the modulator of the calcium channel subunit a2d and the smooth muscle modulator during storage and before administration; e (d) instructions for carrying out drug administration of the calcium channel modulator subunit 2d and the smooth muscle modulator in a manner effective to treat the symptom of a low urinary tract disorder.
67. 67. The packaged kit according to claim 66, characterized in that the modulator of the calcium channel subunit a2d is selected from the group consisting of Gabapentin and Pregabalin and wherein the antimuscarinic is selected from the group consisting of Oxybutynin, Tolterodine, Propiverin and Solifenacin monohydrochloride.
68. 68. The packaged kit according to claim 66, characterized in that the modulator of the calcium channel subunit a2d and the smooth muscle modulator are contained in the same pharmaceutical formulation.
69. 69. The packaged kit according to claim 66, characterized in that the modulator of the calcium channel subunit 2d and the smooth muscle modulator are contained in separate pharmaceutical formulations.
70. 70. The packaged kit according to claim 66, characterized in that the instructions include orientations for carrying out the drug administration of the modulator of the calcium channel subunit to d and the smooth muscle modulator sequentially or concurrently.
71. 71. A packaged kit for use in the treatment of a symptom of a disorder in the lower urinary tract, characterized by comprising: (a) a calcium channel modulator subunit a2d r selected from the group consisting of Gabapentin and Pregabalin; (b) a container containing the modulator of the calcium channel subunit a d during storage and before administration; and instructions for carrying out drug administration of the calcium channel modulator a2d subunit sequentially or concurrently with an antimuscarinic selected from the group consisting of Oxybutynin, Tolterodine, Propiverine and Solifenacin monohydrochloride, in an effective manner to treat the symptom of a disorder of the lower urinary tract.
72. 72. A packaged kit for use in the treatment of a symptom of a disorder in the lower urinary tract, characterized by comprising: (a) an antimuscarinic selected from the group consisting of Oxybutynin, Tolterodine, Propiverine and Solifenacin monohydrochloride; (b) a container containing the antimuscarinic agent during storage and before administration; and instructions for carrying out the administration of antimuscarinic drug sequentially or concurrently with a calcium channel modulator 2d subunit selected from the group consisting of Gabapentin and Pregabalin, in an effective manner to treat the symptom of a low urinary tract disorder.