MXPA98008765A - Combination therapy for erec dysfunction treatment - Google Patents

Abstract

In the field of erectile dysfunction treatment, a novel therapy is described in which the actions of an agent or agents produce a combination of effects to induce effective erection (and avoid priapism) while reducing or totally avoiding pain. The method taught combines a first action of an agent, which is to antagonize a drug-induced pain stimulus within the nociceptive nerves of the tissue of the penis with a second action of either the same agent or a second agent, which increases, in synergistic form, the relaxation of the smooth tissue. The synergism allows at least one equivalent effect of smooth muscle relaxation to be obtained at significantly lower doses of a smooth muscle relaxant such as PGE1 which in standard therapy is also in 40-45% pain-inducing cases in doses which achieve effective erection. Thus, in an anatomical site where the nociceptive tissue is in close proximity to one or more effector systems, the method increases the effector system while reducing nociception in the nociceptive tissue in which nociception can be caused by an agent such as PGE1. , which is used to operate the effective system

Description

COMBINATION THERAPY FOR ERECTI DYSFUNCTION TREATMENT DESCRIPTION OF THE INVENTION The field of the invention is the treatment of erectile dysfunction. In particular, the subject matter of this invention consists of a novel and effective treatment of erectile dysfunction using an agent or agents with actions which combine the properties of (a) preventing the induction of pain and (b) reducing the potential for priapism with increased capacity for muscle relaxation of the corpus cavernosum. Erectile dysfunction (ED) is a significant clinical problem which occurs in up to thirty percent of men in North America. The causes of impotence are usually divided into two non-exclusive categories, that is, organic and psychological. The organic aspects of ED are typically triggered by underlying vascular disease such as that associated with hypertension or diabetes mellitus, may be caused by prescription medications and may include psychiatric illness such as depression. Physiological factors include fear, anxiety of function and interpersonal conflict. ED damages sexual function, decreases self-esteem and alters personal relationships (Padma-Nathan, et al., NEJM, Vol. 336 (1): 1,1997). The human penis is composed of erectile tissue called the corpus cavernosum and spongy body. The cavernous body is comprised of two segments or erectile bodies each located adjacent to the urethra (or spongy body). The erectile tissue is composed of large venous sinuses which contain relatively little blood when the penis is not in the relaxed state but which become fattened by blood when dilated (relaxed). The dilation of these tissues directly contributes to the erection of the penis. The stimulus for a physiological erection originates in the central nervous system. A fully functional natural penile erection requires coordinated change in the exit of several levels of the central nervous system and at least three peripheral nerve groups (sympathetic thoracolumbar, parasympathetic sacral and somatic pelvic). At the level of the tissue of the penis, the location of sympathetic and parasympathetic nerve terminals as well as non-adrenergic, non-cholinergic nerve terminals has indicated the potential involvement of numerous neurotransmitter systems. It is known that the erection of the penis is dependent on the balance and integration between structural control systems (vascular and extracellular matrix) and functional (neural, local and humoral / endocrine factors). The nature of the balance between these contributing influences is ultimately expressed as vasodilatation and tumescence of the penis, as long as there is an adequate level of systematic blood pressure and an appropriate hormonal environment. The vascular components of the penis that have a significant role in the regulation of erectile function are the pudendal arterial system, the cavernous arteries, the corpus cavernosum and the corpus spongiosum and glands. It is well established that erection requires neurally (autonomic) mediated vasodilation of both the arterial blood vessels of the penis and the trabecular matrix. The combined dilation facilitates a rapid initial increase in arterial flow to the corpora cavernosa of the penis, promoting tumescence. This is followed by a phase of flow arrest in which the body tissue expands and comprises sub-tunic veins. This is described as the "veno occlusive mechanism" and this imposes a dramatic increase in the flow resistance which is required to achieve penile rigidity. Conversely, the decease is probably mediated, at least in part, by the activation of the sympathetic nervous system as well as the elimination of the active vasodilator tone. In addition, this may involve changes in local systems. One of the world-accepted interventions used in diagnosis and management The pharmacological treatment of erectile dysfunction involves direct injection of a wide range of vasoactive substances into the corpus cavernosum (penis) for the purpose of producing an erection (intracavernous "IC" injections). More recent strategies involve the provision of a similar range of drugs to the urethra (later to the corpus cavernosum by natural mechanisms) with similar consequences. The currently accepted injectable products are not optimal. Two serious adverse reactions associated with these agents are pain induced by the drug and priapism (ie, inappropriate long-duration erections) (Linet et al., NEJM, Vol. 334: 873 (1996)). It is now known and has been documented in the literature that the single use of prostaglandin El (PGE 1) produces pain response in approximately 3 to 10 percent of individuals who use this therapy. However, it is also known that over time the repeated use of PGEl is associated with a continuous incidence of pain. This is such that 40 to 45 percent of patients who use PGEl multiple times will report pain response with use (Linet et al., NEJM, Vol. 334 (14) 873 (1996)). When such patients use PGEl for a prolonged period of time, it is expected that they may experience pain and this becomes a serious problem which may result in the decreased use of PGEl or switching to alternative therapy. Alternatives currently include surgical intervention (destructive and irreversible, with a success ratio between 31 to 80 percent); vacuum devices (moderate effectiveness, can be difficult for some men who use it and can cause penile trauma); and oral medications (efficacy not tested). Transurethral administration of PGEI or other vasoactive agents is another alternative procedure for injection therapy, although this has resulted in reports of penile pain in 35.7 percent of men who are being treated for clinical tests (Padma-Nathan et al., NEJM, Vol. 336 (1): 1 (1997)). It is understood that only two products have been approved by the United States FDA for the treatment of ED: intracavernous injection using PGEl (Caverject, Upjohn Pharmaceutical, Virilan, Schwarz Pharma) and intraurethral PGEl (MUSE, Vivus Inc. Menlo Park, CA). Thus there is a need to provide a method or therapy for inducing effective erections (and avoiding priapism) while the pain is reduced or totally avoided. The present invention is a therapy in which the combination of actions of an agent or agents induces effective erections (and avoids priapism) while reducing or totally avoiding pain. According to one aspect of the present invention there is provided a method for increasing the actions of cyclic adenosine monophosphate (cAMP) in an effector system while reducing the action of cAMP in a nociceptive system in which the method comprises application of one or more of the various forms of NO, or CO to a site where cAMP exists. According to another aspect of the present invention, a method is provided wherein the cAMP actions are altered by the application of an agent which increases the cyclic guanosine monophosphate (cGMP).

According to another aspect of the present invention, there is provided a method wherein the action of cAMP is disrupted by application of an agent which inhibits phosphodiesterase. In still another aspect of the present invention is provided, at an anatomical site where the nociceptive tissue is in close proximity to one or more effector systems, a method for increasing the effector system while reducing the nociception in the nociceptive tissue comprising modifying the actions of cAMP in the site by application of one or more of the various forms of NO or CO, or that comprises the application of an agent or agents that enhance or increase the action of cAMP in the effector systems and in the nociceptive tissue causes an increase of cGMP in relation to cAMP, which may include a total reduction in cAMP but with relatively more cGMP. According to one aspect of the present invention there is provided a method for increasing penile erection with minimal pain or pain due to the use of one or more agents that can increase or enhance the effect of cAMP as well as increase or enhance the effect of cGMP in both smooth muscle and nerves, regardless of whether the effect is mediated by changes in the systems of adenylyl or guanylyl cyclase or by direct action of NO or CO, or the cyclic nucleotide phosphodiesterases which inactivate these cyclic nucleotides. According to a further aspect of the present invention there is provided a method for increasing penile erection with minimal pain or no pain by the use of an agent which directly or indirectly generates NO and which increases or enhances the effect of cAMP in smooth muscle but not in nerves. According to a further aspect of the present invention there is provided a method for increasing erection of the penis with minimal or no pain by the use of an agent which generates NO in both the smooth muscle and nerves in combination with an agent that increases or potentiates the effect of cAMP on smooth muscle but not on nerves. According to a further aspect of the present invention there is provided a method for increasing penile erection with minimal pain or no pain by the use of any of the following NO donors: glyceryl trinitrate, isosorbide 5-mononitrate, isosorbide dinitrate , pentaerythritol tetranitrate, erythrityl tetranitrate, sodium nitroprusside, 3-morpholinosidnonimine molsidomine, S-nitroso-N-acetylpenicillamine, S-nitrosoglutathione, N-hydroxyl-L-arginine, S, S-dinitrosodithiol, or NO gas, or a functional equivalent thereof in combination with an agent that increases or enhances the effect of cAMP on smooth muscle but not on nerves.

According to a further aspect of the present invention there is provided a method to increase penile erection with minimal pain or no pain by the use of one or more agents which generate NO or CO and which increase or potential the effect of cAMP in smooth muscle but not in nerves. According to a further aspect of the present invention there is provided a method for increasing erection of the penis with minimal pain or no pain by the use of an agent which generates NO in both the smooth muscle and nerves in combination with an agent that increases or potentiates the effect of cAMP on smooth muscle but not on nerves. According to a further aspect of the present invention there is provided a method for increasing erection of the penis with minimal pain or no pain by the use of at least any of the following NO donors: glyceryl trinitrate, isosorbide 5-mononi while , isosorbide dinitrate, pentaerythritol tetranitrate, erythrityl tetranitrate, sodium nitroprusside, 3-morpholinosidnonimine molsidomine, S-nitroso-N-acetylpenicillamine, s-nitrosoglutathione, N-hydroxyl-L-arginine, s, S-dinitrosodithiol, or NO gas , or functional equivalents thereof, in combination with an agent that increases or enhances the effect of cAMP on smooth muscle but not on nerves. According to a further aspect of the present invention there is provided a method for increasing erection of the penis with minimal pain or no pain by the use of any of the following NO donors: glyceryl trinitrate, isosorbide 5-mononitrate, isosorbide dinitrate, pentaerythritol tetranitrate, erythrityl tetranitrate, sodium nitroprusside, 3-morpholinosidinone ina molsidomine, S-nitroso-N-acetylpenicillamine, s-nitrosoglutathione, N-hydroxyl-L-arginine, s, S -dinitrosodithiol, or NO gas, or functional equivalents thereof, in combination with PGEI or another prostaglandin. In yet a further aspect of the present invention there is provided a method for increasing erection of the penis with minimal pain or no pain where these agents are administered by any route that will affect the smooth muscle of the penis. It is a further aspect of the present invention that the methods of this invention are not specific to the penis since the mechanism is relevant to other systems where it is important to avoid nociception and increase efficiency. For example, regional or generalized pain managed by opiates can be compensated for by the addition of NO generators or active compounds (single agent or combination) that alter relative cAMP and cGMP activation. The hypothesis of pain reduction of the present invention results from two independent events which involve actions in two different cellular systems (nerves and smooth muscle). The idea of the present is to combine a first action which is to antagonize the stimulus of pain induced by drug within nociceptive nerves and a second action which is to increase, in synergistic form, the smooth muscle relaxation. This synergism allows at least one effect equivalent to significantly lower doses of the pain-inducing agent (e.g., PGEl) to be obtained again by reducing the potential for pain. It is further expected herein that the novel therapeutic strategy of the present invention results in a decrease in pain induced by cAMP-enhancing agents (e.g., PGEl). It is believed herein that this is done by the antinociceptive actions of increases in cGMP and / or No and / or CO levels and / or relative activities in cAMP and cGMP systems in nociceptive nerves mediated by the second agent (or by a second action of the same agent (Ferreira et al., European Journal of Pharmacology 210: 121 (1991)) It is believed herein that the combined actions of agents which simultaneously increase both cAMP and cGMP and therefore seem to result in increased synergistic in the smooth muscle in those studies, also results in the synergistic increase of the relaxation of the corpus cavernosum and therefore the erectile response.Note however that the combined actions of the agents in the two tissues are in direct contrast: in the The effects of cGMP are antagonistic to the actions of cAMP, while in the smooth muscle cGMP directly potentiates the cAMP effects, although this has not been observed. presumably in the cavernous tissue no pain with such combinations. A specific example of this invention, described herein, includes the use of a combination of an agent which activates the adenylyl cyclase (PGEI) system and an agent, which activates both the guanylyl cyclase system (sodium nitroprusside- NPS) as well as other systems acting independently of guanylyl cyclase. Each of these agents alone causes smooth muscle relaxation. PGEl alone, in concentrations which cause smooth muscle relaxation, can also induce hyperalgesia (ie pain in approximately 40-45% of patients causing discontinuation of use). NPS injected only into the penis does not seem to induce pain but at doses required to produce consistent penile erections suffers from a serious side effect of systematic hypotension not acceptable. Typical clinically effective doses for PGE monotherapy are between 5 and 20 μg. The NPs have only been shown to produce unsuitable penile erections at a dose of 50 μg while reaching 200 μg will induce erections but with significant systematic side effects (Brock et al., J. Urology, Vol. 150: 864, 1993). It is demonstrated hereinafter that the use of a low dose (5 μg) or moderate dose (15 μg) of PGEl combined with a low dose of NPS (50 μg) achieves effective erection without pain. Definitions TNG = glyceryl trinitrate ISMN = isosorbide 5-mononitrate ISDN = isosorbide dinitrate TNPE = pentaerythritol tetranitrate TNE = erythrityl tetranitrate NPS = sodium nitroprusside SIN-1 = 3-morpholinosidnonimine moldsidomine SNAP = S-nitroso-N-acetylpenicillamine SNOG = S- Nitrosoglutationa NOHA = N-Hydroxyl-L-arginine PDE3 = phosphodiesterase type III PGEl = prostaglandin AMPc = cyclic adenosine monophosphate cGMP = cyclic guanosine monophosphate T = Tumescence R = Rigidity "Penis" as used herein can be interpreted to be equally applied to the clitoris since in respect there is a substantial equivalence between the erectile tissue of the penis and clitoris.

"Increase penile erection" as used herein is understood to mean increasing the physical size and improving the stiffness of the penis. "Good quality erection" and "effective erection" are used interchangeably herein to mean adequate for vaginal penetration (i.e., intrusion, or intercourse). "PDE2 and PDEII" are used interchangeably to describe the type three phosphodiesterase which normally degrades cAMP and is inhibited by cGMP. "NO donor" and "NO producing agent" are used interchangeably in this specification and include all compounds which donate NO through biotransformation, compounds which generate NO spontaneously, compounds which spontaneously release NO, or any other compounds which similarly generate NO. "Various forms of NO" as used herein is meant to mean any of NO °, NO +, and NO ", and may include as an alternative CO (carbon monoxide)." Apply various forms of NO "as used in the present includes NO donor or NO producing agents BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a bar graph which shows the increased stiffness of the penis with PGEl in combination with NPS when compared to a dose of PGEl alone. Figure 2 is a bar graph demonstrating the tumescence results of patients receiving PGEI compared to patients receiving PGE1 and sodium nitroprusside in combination Existing and published literature teach little about the novel concepts of the invention proposed in the present (reduction of pain and synergistic penile erection). Some patent literature discusses the use of agents which intend to act increasing the smooth muscle levels of cyclic nucleotides, to say either cyclic adenosine monophosphate (cAMP) or cyclic guanosine monophosphate (cGMP). Agents are discussed which act by stimulating the production of these cyclic nucleotides (for example PGEl or NPs, respectively) or by inhibiting their catabolism (for example phosphodiesterase inhibitors cGMP) in relation to the control of blood vessel function, but are not discussed combinations of agents which can increase both cAMP and GMP simultaneously and affect (reduce or avoid) pain. There is limited scientific literature dealing with agents that affect the levels of cyclic nucleotides and the relationship of these effects to pain mediated by prostanoids. Those studies which have been conducted to examine the issue of analgesia and the use of nitric oxide (NO) as an analgesic have been conducted in models of rat hind legs (European Journal of Pharmacology, Vol 186: 289 (1991); 217: 207 (1992), Vol. 201: 121 (1991) and Vol 217: 225 (1992)). Such studies indicate that a nitric oxide donor can act as an analgesic in the case of hyperalgesia induced by prostaglandin applied subcutaneously (PGE2). However, there is no suggestion that donors can not have any application in the field of erectile tissue dysfunction along with pain management associated with the use of prostaglandins. Indicated uses of NO donors in connection with erectile tissue dysfunction are vasorelaxation (see discussion in U.S. Patent 5,278,192). Indeed, in a study in 1993 by Brock et al. (J. Urology, Vol. 150: 864, (1993)) although vasorelaxation effects of sodium nitroprusside (NPS) are reported, the use of nitric oxide and nitric oxide producing agents is discouraged since significant hypotension can be induced by intracavernosal injection of such agents in doses sufficient to produce an erection. Additionally, Patent 5,439,938 teaches methods and devices for reversing the. pain associated with priapism providing inhibitors of NO synthase. Literature that relates to vasodilation but not penis supports the understanding of the present invention that the use of cGMP level enhancers such as NO (which is believed to activate guanylyl cyclase) and cAMP level enhancers such as prostaglandins (which is believed to activate adenylyl cyclase), can cause synergistic vasodilation (Molecular Pharmacology Vol. 37: 671 (1990); and in the European Journal of Pharmacology, Vol. 192: 235 (1991); Vol. 191: 471 (1990); and Vol. 250: 477 (1993)). The hypothesis of the mechanism of synergism has been made that it is due to the increased total concentrations of cAMP through the inhibitory effects of cGMP on phosphodiesterase type III (PDE3). It is believed that PDE3 is responsible for the decomposition of cAMP. However, there is no indication of what effect such combinations may have on pain. Indeed, in view of the literature cited above regarding investing priapism with NO synthase inhibitors, as well as analgesia and NO studies, increases in cAMP can be expected, either by increasing the presence of cAMP or decreasing the decomposition of cAMP, to increase pain. There is also no literature that considers what impact, if any, may have on such erectile function such a combination of agents in the corpus cavernosum. Despite this, it is known to use combination therapies to achieve erection erection while trying to avoid pain, but rely on additive vasodilation.

For example, a report by B. vonHeyden et al. (Journal of Urology Vol. 149: 1288 (1993)) indicates that intracavernous therapy supports the use of prostaglandins (PGEl) introduced intracavernously by injection (ICI). This study reports the use of PGEl and papaverine and phentolamine in combination as a means to reduce one of the main side effects when using prostaglandins, to say pain. As discussed above, pain occurs in 40-45% of patients during prolonged use of PGEl. Although the cause of pain is currently unknown, a report in the European Journal of Pharmacology (Vol 217: 225, 1992) suggests that the sensitization of nociceptors by PGE2 or sympathomimetic amines is due to the activation of adenylate cyclase with a consequent increase in intracellular levels of cAMP / Ca2. The suggestion made in the vonHeyden study is that to reduce the probability of occurrence and degree of pain, it is appropriate to reduce the level of prostaglandins used. This concept simply applies conventional principles of pharmacology, that is, less drug will cause less effect, in this case pain. The loss in erectile function effect is compensated for by reducing the prostaglandins by the other agents in combination therapy. While reference is made to the possibility of synergism between PGEl, papaverine and phentolamine, nothing is taught regarding the use of a second agent which has the effect of reducing the pain associated with the use of prostaglandins while concomitantly providing a synergistic erectile response . This technique teaches that the use of PGEl at concentrations in the order of 10-40 μg (the range of previously accepted treatment) causes pain. A study by Hempelmann, R.G. et al. (European Journal of Pharmacology Vol 276: 277 (1995)) addresses the question of whether vasoactive intestinal peptide (VIP) and NO donors are capable of exerting a synergistic effect on isolated cavernous arteries and corpus cavernosum. The results of the study indicate that PIV is not capable of provoking concentration-dependent relaxation responses, whereas, in contrast, 3-morpholinosidnonimine molsidomine (SIN-1) has the capacity to induce complete relaxations. The study demonstrates that PIV and SIN-1 exert non-synergistic independent relaxing effects in human cavernous arteries and cavernous smooth muscle. Consequently the study argues against a combined therapeutic administration of these two agents. An additional study by Martinez-Pineiro, L. et al.

(Journal of Urology Vol 153: 1487 (1995) discusses the intracavernous injection of vasoactive drugs and lists those commonly known agents such as papaverine, phentolamine and PGEl and the possibility of therapy with a combination of these drugs. report, is the consideration of the mechanism of action of agents similar to prostaglandins that cause pain and it is theorized that the activation is through adenylyl cyclase, which can have the effect of increasing cAMP levels. suggested for pain as discussed above with respect to NO However firm conclusions are not reached regarding the treatment of side effects of such therapies or associated pain, consequently, the use of combinations has not been successful in alleviating pain associated with the use of substances such as PGEl. Specifically, it has been shown that the use of prostaglandin c compounds Non-specific acting compounds such as papaverine and phentolamine are associated with an increased incidence of priapism with pain. In contrast, the combination therapy of the present invention induces effective erections while reducing or totally avoiding pain. Experimental Two series of experiments are performed with the results presented later. The first series (A. Not prior to PGEI) is a group of patients who have not previously used PGEI., and in this way there is little expectation of pain response with respect to the administration of PGEl. The expectation of a pain response in this series of patients, based on the literature, is a frequency of pain per injection in the order of 3 to 10 percent. Although this may be within the standard deviation of the experiments as demonstrated below, the results indicate that none of the patients experience any pain. Not only is there no pain, the response of PGEl is significantly increased by the use of the NO donor, (in this case, sodium nitroprusside (NPS)). This increased response is usually associated with higher doses of PGEl and with such higher doses, there is associated pain pain. The second series of patients (B. before the use of PGEl) who are part of this study have a clinical history of pain in association with the use of prostaglandin therapy where this therapy is used for the purpose of obtaining penile erection. As shown below, the results of this series indicate that all patients after receiving a reduced dose of PGEl experience reduced pain or no pain at all erections of the penis and increased despite the reduction in the dose of PGEl, General methods : Erectile dysfunction (ED) clinical laboratory measurements are made in patients with previously diagnosed ED. These patients are being evaluated for the purpose of optimizing their dosage for intracavernous injection. All men are evaluated using the Human Sexuality Group Protocol of Queen's University (Kingston, Ontario, Canada).

A. Not prior to PGEl Patients are fixed with the Rigiscan ™ tumescence device and rigidity record. Patients are injected with the intracavernous drug (IC) using up to 2 different doses (PGEl alone or in combination with sodium nitroprusside (NPS50 μg)) and monitored for real time of their erectile response. Patients are given only a second injection (higher dose PGEI) only if the response to the first injection is less than 70% maximum tumescence and stiffness. In addition, patients are asked to report any occurrence of pain specific to the injection, but it is not related to acute discomfort associated with the sting of the needle. Initial inclusions Men with known erectile dysfunction characterized by a three-month history. Exclusions 1. Patients who respond to IC injection with total tumescence at the lowest dose of PGEl alone. 2. Patients in whom there are no significant responses at any dose (revealing a high degree of organic disease). 3. Patients in whom there is a technical problem with measurements (incomplete data). Two phases of the evaluation of the optimization protocol: Phase 1: (n = 9) First visit - IC injection of PGEl 5 μg IC Second visit - IC injection of PGEl 5 μg + NPS 50 μg Phase 2: (n = 12) First visit - IC injection of PGEl 5 μg IC - after (15 min.) PGEl 15 μg IC Second visit - injection IC of PGEl 5 μg + NPS 50 μg - after (15 min.) PGEl 15 μg + NPS 50 μg RESULTS: Erectile responses: Phase 1 is performed to validate the known effects of low dose PGEl and confirm the safety margin using NPS (Lue et al., Journal of Urology 150: 864-867 (1993)). In 4 of 9 patients there is a poor response to both injections. 2/9 experience total tumescence with the lowest dose of PGEl alone. 3/9 show moderate to substantial improvement with the combination. In only one patient, who has a moderate response to a low dose of PGEl alone, there is no increase. The data from this study confirm that in a number of patients higher doses of PGEl alone or in combination are required to induce the erectile response. Based on this finding, the protocol is changed to include higher doses of PGEl. In Phase 2 of the protocol four formulations are developed: The first PGEI (5 μg in 1 ml of saline), the second, a higher concentration of PGEI (15 μg in 1 ml of saline), the third PGEl + NPS ( 5 μg + 50 μg in 1 ml of saline) and the fourth PGEl + NPS (15 μg + 50 μg in 1 ml of saline). In phase 2 of the study, 12 patients are evaluated. Total data are available in 10 of these (see below Figure 1, where the ordinary represents% rigidity units, and Figure 2). 3 of these 10 develop total responses to 5 + 15 μg of PGEl alone. For the rest of the 7 patients there is a significant increase in all patients (p <0.05) when combined with NPS. None of these patients experience any pain related to the drug with these treatments. B. Before the use of PGEl Patients who are part of this study have a clinical history of pain in association with the use of prostaglandin therapy where this therapy is used for the purpose of obtaining penile erection. As detailed later, one of three different modes of administration of NO producing agents depending on the patient is used. In particular, each of these individuals receives a NO donor either through the use of a nitroaspersor such as Nitrolingual ™ or a transdermal patch that delivers a NO-donor compound, and in all three cases, a combination of PGEI and 50 μg of NPS (in saline or phosphate buffered saline (SAF)). The results of these treatments are detailed below. Case No. 1 DB, aged fifty-five years, underwent a radical perineal prostatectomy in October 1996. The patient was observed in the Injection Clinic in February 1997. He was given 5 μg of PGEl and then 5 μg of additional PGEl. in fifteen minute intervals. After the second injection, you have pain in your penis for a duration of about fifteen minutes. DB uses a nitro-sprinkler (Nitrolingual ™) on a regular basis and is asked to use it at the injection time with PGEl and the response is recorded on his penis. He takes an oral spray and reports improvement within two minutes of all the discomfort of the penis. The erection is of good quality and is maintained. The patient reports that this erection may be adequate for intercourse. The erection is attested. Case No. 2 CC, aged seventy-one, underwent radical perineal prostatectomy in January 1996 and was observed in October 1996 and is currently using 10 μg of PGEl at home with pain and poor response. It is observed in the clinic and a transdermal patch is prescribed that supplies a compound of NO donor at a rate of 0.2 mg / hour placed twenty minutes before the injection. 10 μg of PGEl is injected. The patient does not report pain and gets good enough erection for the desired intercourse to be left alone. The erection is attested. Case no. 3 GH, fifty-four years of age, suffered from radical perineal prostatectomy in October 1996. During the course of his recovery he reports some spontaneous erections and some induced pharmacologically. It is observed in February 1997. The patient reports that the home use of PGEl produces pain in the penis unless it precedes the use of Nitropatch 0.2 mg / hour ten minutes before the injection or sexual response. Case no. 4 JB, fifty-four years old, underwent radical perineal prostatectomy in September 1995, reported pain with intracavernous injection of PGEl. In May of 1996, he uses 20 μg of PGEl with 50 μg of NPS and he reports that the NPS "decreases the pain". Case no. 5 Another JB, aged seventy-one, with multifactor erectile dysfunction, reports pain with intracavernous injection of PGEI lasting three to four hours. In May of 1996 he receives 20 μg of PGEl with 50 μg of NPS, repeated fifteen minutes later (20 μg of PGEl + 50 μig of NPS) without producing burn and a response judged by the patient and an experienced nurse to be at least 75%, that is, total erection. Case no. 6 TW, fifty-eight years of age, with radical perineal prostatectomy in 1996 reported frequent pain at home with PGEl. In March 1997, 10 μg of PGEl and 50 μg of NPS repeated fifteen minutes later with 10 μg of PGEl and 50 μg of NPS do not produce burn and have substantial efficacy, say a total erectile response. The concentration of glyceryl trinitrate (the typical form of NO donor derived from glyceryl trinitrate) has been reported.

Nitroaspersor or Nitroparches) in the literature for such delivery routes to be in the order of 200 to 400 picograms per milliliter (pg / ml) of plasma (Sun et al, J. Clin. Pharmacol. (35) 390, 1995). While the routes of administration of PGEl and NO donors reported herein include IC injection of prostaglandin and injection IC of NO donor, or by nasal spray or patch, the present invention includes administration by means of topical creams, organic carrier substances and pharmaceutically acceptable inorganics suitable for parental, enteral, intraurethral or intranasal application which which do not react in a harmful manner with the active compounds. The compositions of the invention are administered to subjects in a biologically compatible form suitable for pharmaceutical administration in vivo. By "biologically compatible form suitable for in vivo administration" is meant a form of the active compounds of the invention to be administered in which any toxic effects are assessed by the therapeutic effects of the active compounds of the invention. The term subject is proposed to include living organisms in which a response may be produced, e.g., mammals. Examples of subjects include humans, dogs, cats, mice, rats and transgenic species. thereof. The administration of a therapeutically active amount of the therapeutic compositions of the present invention is defined as an effective amount, in doses and periods of time necessary to achieve the desired result. For example, a therapeutically effective amount of active compounds of the invention may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the agent or combination of agents of the invention to produce a desired response in the individual. Dosage regimens can be adjusted to provide the optimal therapeutic response. For example, several divided doses may be administered or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where they are soluble in water) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the composition must be sterile and must be fluid to the extent that there is ease of handling in a syringe. It must be stable under the conditions of manufacture and storage and must be preserved against the action of contamination of microorganisms such as bacteria and fungi. The pharmaceutically acceptable carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (eg, glycerol, propylene glycol and liquid polyethylene glycol, and the like), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, for the maintenance of the required particle size in the case of dispersion and for the use of surfactants. The prevention of the action of microorganism can be achieved by various anti-bacterial and anti-fungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, imerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, and sorbitol or sodium chloride in the composition. Prolonged absorption of the injectable compositions can be accomplished by including in the composition an agent which retards absorption, for example, aluminum monostearate and gelatin. Sterile injectable solutions can be prepared by incorporating active compounds (e.g., NPS and PGEI) in the required amount in an appropriate solvent with one or a combination of ingredients listed above, as required, followed by filter sterilization. Generally, dispersions are prepared by incorporating the active compound in a sterile vehicle which contains a basic dispersion medium and the other ingredients required from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and drying-freezing which produces a powder of an active ingredient of the invention plus any additional desired ingredient of a solution previously sterilized by filtration of it. When an active compound is suitably protected, as described above, the composition can be administered orally, for example, with an inert diluent or an edible assimilable carrier. As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption retardant agents, and the like. The use of such media and agents in pharmaceutically active substances is well known in the art. Except insofar as any conventional means or agent is incompatible with the active compound, use thereof in the therapeutic compositions is contemplated. Complementary active compounds can also be incorporated into the compositions. It is especially advantageous to formulate parental compositions in the dosage unit form for ease of administration and dose uniformity. The dosage unit form as used herein refers to physically discrete units suitable as unit doses for mammalian subjects to be treated; each unit containing a predetermined amount of the active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and (b) the inherent limitations in the technique of formation of composition of an active compound for the therapeutic treatment of individuals. While describing and understanding that the method of this invention includes the combination of NO and PGEI donors, the invention includes the combination of NO donors and other analgesics such as opiates, non-spheroidal anti-inflammatory drugs, such as ibuprofen, naproxen, and acid. mafanámico, to produce a synergistic decrease in pain. While the invention has been particularly shown and described with reference to certain embodiments, it will be understood by those skilled in the art that various other changes in form and detail may be made without departing from the spirit and scope of the invention. All reference documents and patents referred to for this specification are incorporated in their entirety for reference herein.

Claims (22)

1. CLAIMS 1. A method for increasing the actions of cAMP in one or more effector systems while reducing the action of cAMP in a nociceptive system in an anatomic site where the nociceptive tissue is in close proximity to one or more effector systems characterized in that it comprises application of one or more agents which increase the level or increase the effect of cGMP.
2. 2. A method for increasing the actions of cAMP in one or more effector systems while reducing the action of cAMP in a nociceptive system in an anatomical site where the nociceptive tissue is in close proximity to one or more effector systems characterized in that it comprises application of one or more of the various forms of NO or CO.
3. 3. A method for increasing the actions of cAMP in one or more effector systems while reducing the action of cAMP in a nociceptive system at an anatomical site where the nociceptive tissue is in close proximity to one or more effector systems characterized in that it comprises application of one or more agents that increase or enhance the effects of cyclic nucleotides by modulating the activities of cyclic nucleotide phosphodiesterases.
4. 4. A method for increasing the actions of cAMP in one or more effector systems while reducing the action of cAMP in a nociceptive system at an anatomical site where the nociceptive tissue is in close proximity to one or more effector systems characterized in that it comprises application of at least one agent that enhances or increases the action of cAMP in the effector systems and, in the nociceptive system, causes an increase in cGMP with respect to cAMP, such that there is a total reduction of cAMP but with relatively more cGMP.
5. 5. The method according to claim 3, characterized in that the alteration of cAMP actions is caused by the application of a peptide which inhibits phosphodiesterase in smooth muscle and activates cAMP phosphodiesterase in nervous tissue.
6. 6. The method according to any of the preceding claims characterized in that the anatomical site is engordable genital tissue.
7. 7. The method according to claim 6 characterized in that the anatomical site is the penis.
8. 8. The method according to claim 6 characterized in that the anatomical site is the clitoris.
9. 9. A method for increasing erection of the penis or clitoris characterized in that it comprises the use of at least one agent in an effective amount that can increase the effect of cAMP as well as increase the effect of cGMP with minimal pain or no pain.
10. The method according to claim 9 characterized in that one or more agents can increase the cAMP effect in smooth muscle as well as increase the cGMP effect in nervous tissue.
11. The method according to claim 9 characterized in that one or more agents increase the effect of cAMP by stimulating the adenylyl cyclase and / or by inhibiting the activity of the cyclic nucleotide phosphodiesterase in smooth muscle while increasing the effect of cGMP on nervous tissue.
12. 12. The method according to claim 9, characterized in that the at least agent increases the effect of cGMP and inhibits the cyclic nucleotide phosphodiesterase generating nitric oxide.
13. 13. The method according to the claim 11 or claim 12 characterized in that the cyclic nucleotide phosphodiesterase is PDE3.
14. 14. The method according to the claim Characterized in that one or more agents are selected from the group consisting of glyceryl trinitrate, isosorbide 5-mononitrate, isosorbide dinitrate, pentaerythritol tetranitrate, erythrityl tetranitrate, sodium nitroprusside, 3-morpholinosidnonimine, molsidomine, S-nitroso-N- acetylpenicillin, S-nitrosoglutathione, N-hydroxy-L-arginine, S, S-dinitrosodithiol and NO gas.
15. The method according to any of the preceding claims, characterized in that one or more agents are supplied by any route that will affect the smooth muscle and nerves in the engordable genital tissue.
16. 16. The method according to claim 9, characterized in that two agents are used and the agent that can increase the effect of cGMP does so by generating NO or CO.
17. 17. The method according to claim 9 characterized in that two agents are used, one of the agents increases the effect of cAMP by stimulating adenylyl cyclase in smooth muscle and the second of the agents inhibits the nucleic acid cyclic phosphodiesterase in smooth muscle.
18. 18. The method of compliance with the claim Characterized in that the cyclic nucleotide phosphodiesterase is PDE3.
19. 19. The method according to claim 16 characterized in that the agent which generates NO is selected from the group consisting of glyceryl trinitrate, isosorbide 5-mononitrate, isosorbide dinitrate, pentaerythritol tetranitrate, erythrityl tetranitrate, sodium nitroprusside, -morpholinosidnonimine, molsidomine, S-nitroso-N-acetylpenicillin, S-nitrosoglutathione, N-hydroxy-L-arginine, S, S-dinitrosodithiol and NO gas.
20. The method according to claim 9 characterized in that the agent that increases or enhances the cAMP effect is selected from the group consisting of PGEl, PIV, forskolin, acetylcholine and peptide related to the calcitonin gene.
21. 21. The method according to claim 9 characterized in that one or more agents are delivered by any route that will affect the smooth muscle and nerves of the penis or clitoris.
22. 22. In an anatomical site where the nociceptive tissue is in close proximity to one or more effector systems, a method for increasing the effector system while reducing nociception in the nociceptive tissue is characterized in that it comprises the application of an agent or agents that enhance or increase the action of cAMP in the effector systems and in the nociceptive tissue causes an increase of cGMP in relation to cAMP.