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    • 专利摘要:
    PURPOSE: A novel therapy is provided to induce effective erection and avoid priapism while reducing or entirely avoiding pain. CONSTITUTION: The synergism allows for at least an equivalent effect of smooth muscle relaxation to be obtained at significantly lower doses of a smooth muscle relaxing agent such as PGE1 which in standard therapy is also in 40-45% of cases inducing pain at doses which achieve effective erection. Thus, in an anatomical site where nociceptive tissue is in close proximity to one or more effector systems, the method enhances the effector system while reducing nociception in the nociceptive tissue which nociception would be caused by an agent such as PGE1 which is used to trigger the effector system. A therapy for treatment of erectile disfuction combines a first action of an agent which is to antagonize a drug induced pain stimulus within nociceptive nerves of penile tissue with a second action of either the same agent or of a second agent, which enhances, synergistically, smooth muscle relaxation.
    公开号:KR20000005455A
    申请号:KR1019980708223
    申请日:1997-04-23
    公开日:2000-01-25
    发明作者:마이클 에이. 아담스；더블유. 히튼 제레미 피.；도날드 에이치. 마우리스
    申请人:퀸즈 유니버시티 엣 킹스턴；마우리스 도날드 에이치；
    IPC主号:
    专利说明:

    Complex treatment of erectile dysfunction
    Erectile dysfunction (ED) is an important clinical problem that affects up to 30% of North American men. Causes of sexual intercourse can usually be divided into two general categories: organic diseases and psychogenic diseases. Disorders of ED are usually caused by underlying vascular diseases, such as hypertension or diabetes mellitus, and may be caused by prescription drugs or by mental illnesses such as depression. Psychological factors may include fear, performance worries and interpersonal conflict. ED impairs sexual activity, reduces self-esteem, and destroys interpersonal relationships (Padma-Nathan, et al. NEJM, Vol. 336 (1): 1, 1997).
    The penis of a human male consists of erectile tissue called penile cavernous bodies and urethral cavernous bodies. The corpus cavernosum consists of two parts of the erection located adjacent to the urethra (or urethral cavernos). The erectile tissue consists of large venous sinuses that contain a relatively small amount of blood when the penis is not in an inflated state, but in the inflated state the blood is congested. This expansion of the erectile tissue contributes directly to the penis erection.
    Stimulation for physiological erection comes from the central nervous system. Full-featured natural penile erection requires multiple levels of central nervous system output and cooperative changes in at least three sets of peripheral nervous system (waist sympathetic nervous system, sacral parasympathetic nervous system and pelvic cavity). At the level of penile tissue, the location of sympathetic and parasympathetic nerves as well as non-adrenal, non-choline sympathetic nerves indicates the potential for involvement of multiple neurotransmitter systems. Penile erection is known to rely on balance and integration between structural and functional control systems. As long as there is an adequate level of tissue blood pressure and an appropriate hormonal environment, the nature of the balance between their contributions is ultimately expressed in vasodilation and penis swelling. The blood vessel parts of the penis that play an important role in regulating erectile function are the vulva artery system, the arterial body, the cavernous artery, the corpus cavernosum and the urethral cavernous body and the glan.
    An erection requires nerve-controlled (autonomic) vasodilation for both penile artery vessels and trabecular nets. Due to this combined vasodilation, the inflow of arterial blood flow into the corpus cavernosum of the penis is easy to initially increase, and the expansion of the penis is facilitated. Thereafter, the penile body tissue expands and decreases inflow as it compresses the veins under the envelope. This is called the veno-occlusive mechanism, which forces a significant increase in the inflow resistance needed to harden the penis. Conversely, detumescence seems to be at least partially regulated by activating the sympathetic nervous system as well as eliminating active vasodilator tone. Moreover, it can include changes in the local system. One of the widely accepted interventions used in the diagnosis and medication of erectile dysfunctions involves the direct injection of various vasoactive substances into the corpus cavernosum (penis) for erection (intracavernosal IC injection). The new method has similar results and delivers a similar range of drugs to the urethra (which is then delivered to the cavernous spongy body by natural mechanism). Two serious adverse reactions associated with these agents are drug-induced pain and sustained erection (ie, erections last inadequately long) (Linet, et al. M NEJM. Vol. 334: 873 (1996)). It is now well known that when using prostagladin E1 (PGE1) alone, it causes pain response in about 3 to 10% of the subjects and is also disclosed in the literature. It is also known that pain continues to be caused by prolonged repeated use of PGE1. This indicates that 40-45% of patients who have used PGE1 multiple times have experienced pain response from the drug (Kine et al., NEJM. Vol. 334 (14) 873 (1996)). If such a patient has used PGE1 for a long time, they may experience pain and for this reason can expect that the use of PGE1 will be a serious problem that the use of PGE1 will decrease or switch to other alternative therapies. Current alternative therapies include surgical methods (destructive, irreversible, success rates 31-80%); Vacuum device (medium efficiency, may be difficult to use for some people and may cause trauma to the penis); And oral medications (not proven effective). Although 35.7% of those who participated in clinical trials reported pain in the penis, transurethral administration of PGE1 or other vascular agonists was another alternative to injection therapy (Padma-Nathan et al. , NEJM, Vol. 336 (1): 1 (1997)). Currently, only two products have been approved by the US FDA for ED treatment: injection of PGE1 into intracranial nodal (Caverject, Upjihbn Pharmaceutical: Virilan, Schwarz Pharma) and urethra (MUSE, Vivus Inc) using PGE1. Menlo Park, CA).
    Thus, there is a need to provide a method or treatment for causing effective erection (without erection persistence) while reducing or eliminating pain completely.
    Summary of the Invention
    The present invention is directed to agents that combine effective action or agents that cause effective erection (without erection persistence) while reducing or completely eliminating pain.
    According to one aspect of the invention, there is provided a method of reducing the action of cAMP in a noxious system while increasing the action of cyclic adenosine monophosphate (cAMP) in an effector system, the method comprising one or more of Application of the form NO or CO to the site where said cAMP is present.
    According to one aspect of the invention, the invention provides a method of altering the action of cAMP by applying an agent that increases cyclic guanosine monophosphate (cGMP).
    According to one aspect of the invention, the invention provides a method of altering cAMP action by applying an agent that inhibits phosphodiesterase.
    In another aspect of the invention, at an anatomical site in which the nociceptive tissue is located very close to at least one effector system, a method of reducing irritation of the nociceptive tissue but increasing the effector system, wherein The application of one or more of various forms of NO or CO consists of altering the action of cAMP, or increases or elevates the action of cAMP in the effector system. The method consists of applying agents or agents that increase cGMP relative to cAMP, which may contain many, and the penis and clitoris are examples of such anatomical sites.
    According to another aspect of the present invention, the present invention provides the effect of adenyl cyclase or guanyl cyclase by using one or more agents that can increase or increase the effect of cAMP as well as cGMP in both smooth muscle or nerve. How to promote penile erection without minimal pain or pain, regardless of changes in the system, or the direct action of NO or CO, or controlled by cyclic nucleotide phosphodiesterases that inactivate such cyclic nucleotides to provide.
    According to another aspect of the present invention, the present invention provides a method for promoting penile erection without minimal pain or pain by using an agent that directly or indirectly produces NO and increases or enhances the effect of cAMP in smooth muscle, but not in the nerves. To provide.
    According to another aspect of the invention, the present invention is free of minimal pain or pain by using agents that increase or enhance the effect of cAMP in smooth muscle, but not in the nerve, by using agents that produce NO in both smooth muscle and nerve. Provides a way to improve penile erection.
    According to another aspect of the invention, the invention provides penile erection with minimal pain or pain by using any of the following NO donors, in combination with agents that increase or enhance the effect of cAMP in smooth muscle, but not in the nerves Provide a way to improve; Glyceryl Trinitrate, Isosorbide 5-Mononitrate, Isosorbide Dinitrate, Pentaerythritol Tetranitrate, Eritrityl Tetranitrate, Sodium Nitroprusside, 3-morpholinosidenonimine molydomido , S-nitroso-N-acetylphenicylamine, S-nitrosoglutathione, N-hydroxy-L-arginine, S, S-dinitrosodithiol or NO gas, or equivalent.
    According to another aspect of the present invention, the present invention improves penile erection with minimal pain or pain by using one or more agents that produce NO or CO and enhance or enhance the effect of cAMP in smooth muscle, but not in the nerves. Provide a method.
    According to another aspect of the invention, the present invention is free of minimal pain or pain by using agents that increase or enhance the effect of cAMP in smooth muscle, but not in the nerve, by using agents that produce NO in both smooth muscle and nerves. It provides a method for promoting an erection of the penis.
    According to another aspect of the present invention, the present invention is directed to a penis without minimal pain or pain by using at least one of the following NO donors, in combination with an agent that increases or enhances the effect of cAMP in smooth muscle, but not in the nerve. Provided are methods for improving erection: glyceryl trinitrate, isosorbide 5-monitrate, isosorbide dinitrate, pentaerythritol tetranitrate, erytrityl tetranitrate, sodium nitroprusside, 3-morpholinosidenonimine molsidodomine, S-nitroso-N-acetylphenicylamine, S-nitrosoglutathione, N-hydroxy-L-arginine, S, S-dinitrosodithiol or NO gas, Or acting equivalent to them.
    According to another aspect of the present invention, the present invention provides a method for promoting erection of the penis with minimal pain or no pain by using any of the following NO donors, in combination with PGE1 or other prostaglandins: Glyceryl Trinitrate, Isosorbide 5-Mononitrate, Isosorbide Dinitrate, Pentaritritol Tetranitrate, Eritrityl Tetranitrate, Sodium Nitroprusside, 3-Morphocinoside Nonnimine Molydomido , S-nitroso-N-acetylphenicylamine, S-nitrosoglutathione, N-hydroxy-L-arginine, S, S-dinitrosodithiol or NO gas, or equivalent.
    In another aspect of the present invention, the present invention provides a method of improving the erection of the penis with minimal pain or no pain by using an agent delivered by any route affecting the smooth muscle of the penis.
    In another aspect of the present invention, the method of the present invention is not specific to the penis in mechanisms involving other systems where elimination of uptake and enhancement of efficacy is important. For example, local or systemic pain controlled by an opiate will be offset by the addition of an active compound (alone or combination agent) that alters NO production or relative activity of cAMP and cGMP.
    The pain reduction according to the invention can be assumed to be the result of two different independent events related to the action of two other cellular systems (smooth muscle and nerve). Our idea is to combine the first action to counteract drug-induced pain stimulation in the receptive nerve and the second to synergistically increase swelling of smooth muscle. This synergy is believed to be at least equivalent to what can be obtained with a pain-inducing agent (eg, PGE1), which reduces the incidence of pain in significantly lesser amounts.
    We also anticipate that the pain caused by cAMP enhancers (eg PGE1) will be reduced as a result of the novel therapy according to the present invention. We believe that this is due to an increase in cGMP and / or NO and / or CO and / or a second agent (or by a second action of the same agent (Ferreira et al., European Journal of Pharmacology 201: 121 (1991) It is believed to be achieved by anti-irritation by increasing the relative activity of cAMP and cGMP in the stimulatory nerves regulated by))). It is believed that the combined action of the agent (s), which simultaneously increases both cAMP and cGMP, results in a synergistic increase in smooth muscle, also results in a synergistic increase in the expansion of the corpus cavernosum, resulting in an erectile response. However, the combined actions of the agent (s) in the two tissues are in direct contrast: it should be noted that cGMP in neurons directly antagonizes the action of cAMP, whereas in smooth muscle cGMP directly enhances the effect of cAMP. Despite this fact, surprisingly no pain was observed in the corpus cavernosum tissue as a result of such a combination.
    In specific embodiments of the invention described herein, the guanyl cyclase system can be activated as well as an agent that activates the adenyl cyclase system (PGE1) and other systems that act independently of guanyl cyclase. The use of a combination of agents (sodium titroproside-SNP). These agents alone cause swelling of smooth muscle. PGE1 alone can also cause hyperalgesia (ie, about 40-45% of patients discontinue use because of pain) at concentrations that can cause smooth muscle swelling. SNPs injected into the penis alone do not cause pain but suffer from serious side effects such as unacceptable tissue hypotension at the concentrations needed to cause persistent penile erections. Generally, effective dosages for PGE1 monotherapy are 5-20 μg. SNPs alone resulted in inadequate penile erection at 50 μg, which would cause an erection when approaching 200 μg but would have serious tissue side effects (Brock et al. J. Urology, Vol. 150: 864, 1993). We explain as follows. Combined with low dose SNP (50 μg), low dose (5 μg) or medium dose (15 μg) PEG1 can achieve effective erection without pain.
    Justice
    GTN = Glyceryl Trinitrate
    ISMN = isosorbide 5-monnitrate
    ISDN = isosorbide dinitrate
    PETN = pentaerythritol tetranitrate
    ETN = eryryltrityl tetranitrate
    SNP = Sodium Tropruside
    SIN-1 = 3-mololinosidnonnimine molecidomin
    SNAP = S-nitroso-N-acetylphenylsilamine
    SNOG = S-nitrosoglutathione
    NOHA = N-hydroxy-L-arginine
    PDE3 = phosphodiesterase type III
    PGE1 = prostagladin E1
    cAMP = cyclic adenosine monophosphate
    cGMP = cyclic guanosine monophosphate
    T = expansion
    R = rigid
    As used herein, "penis" can be interpreted to apply equally to the clitoris which is substantially equivalent between the penis and clitoris erectile tissue.
    As used herein, "erection of good quality" and "effective erection" mean appropriate for vaginal passage (ie, insertion or intercourse) and can be used interchangeably.
    "PDE3" and "PDEIII" are intended to describe phosphodiesterase type 3 which can normally degrade cAMP and be inhibited by cGMP and can be used interchangeably.
    "NO donor" and "NO producing agent" are used interchangeably herein and include all compounds that provide NO by biological conversion, compounds that spontaneously produce NO, spontaneously release NO. Compounds or other compounds that produce NO.
    As used herein, "various forms of NO" are understood to mean any of NO °, NO + , NO - and include CO (carbon monoxide) as a substitute.
    As used herein, "applying various forms of NO" includes NO donors or NO generators.
    The present invention relates to the treatment of erectile dysfunction. More specifically, the present invention provides an agent that functions in combination with (a) preventing the occurrence of pain and (b) reducing the likelihood of sustained erection with increased swelling (penis erection) ability of the cavernous smooth muscle. Agents are used to make new and effective treatments for erectile dysfunction.
    1 is a bar graph illustrating the increase of the firmness of the penis when SNP and PGE1 are used in combination with the use of PGE1 alone.
    FIG. 2 is a bar graph illustrating the expansion results obtained from patients receiving PGE1 compared to patients receiving both PGE1 and sodium nitroprusside.
    Very little is exemplified in the existing patents and published literature regarding the novel concept of the invention presented here with reduced pain and synergistic penile erection. Some patent documents disclose the use of agents that have the effect of increasing levels of cAMP or cGMP in cyclic nucleotides, ie, smooth muscle. Regarding the regulation of vascular function of agents that stimulate the production of these cyclic nucleotides (e.g., PGE1 or SNP, respectively) or agents that inhibit their degradation (e.g. cGMP phosphodiesterase inhibitors) Although mentioned, there is no mention of a combination agent that can simultaneously increase both cAMP and cGMP and affect (reduce or eliminate) pain.
    The scientific literature dealing with agents affecting cyclic nucleotide levels and their effects on prostanoid-controlled pain is limited. Studies have been conducted to investigate the use of nitric oxide as an analgesic and analgesic in rat hind paw models (European Journal of Pharmacology, Vol 186: 289 (1991; Vol 217: 207 (1992); Vol 201: 121 (1991) and Vol 217: 225 (1992)) These studies suggest that carbon monoxide donors can act as analgesics for the hypersensitivity caused by subcutaneous application of prostaglandin E2 (PGE2). With regard to the control of pain in women, such studies did not imply that NO donors could be applied in the field of dysfunction of erectile tissues.The suggested use of NO donors for dysfunction of erectile tissues is vasorelaxation. (See US Patent 5,278,192) Indeed, in a 1993 study by Brock et al. (J. Urology, Vol. 150: 864, (1993)), although the vasodilating effect of sodium nitroprusside (SNP) was reported. Been In addition, the use of nitric oxide and nitric oxide generating agents is discouraged because significant hypotension can be induced by injecting sufficient dose into the penile tissue to induce erection, and patent 5,439,938 also discloses inhibitors of NO synthase. Provided are methods and apparatus for reversing pain associated with erectile dysfunction.
    The scientific literature on non-penis vasodilation is our understanding of the present invention, namely the use of cGMP level increasing agents such as NO (believed to be the activation of guanyl cyclase) and the level of cAMP such as prostaglandins It is supported that the use of increasing agents (believed to be the activation of adenyl cyclase) can cause synergistic vasodilation (Molecular Pharmacology Vol 37: 671 (1990); Vol 250: 477 (1993)). This mechanism of synergy is assumed to be due to an increase in the overall concentration of cAMP due to the inhibitory effect of cGMP on phosphodiesterase type III (PDE3). It is believed that PDE3 is responsible for the degradation of cAMP. However, no indication is made about the effect of such binding on pain. Indeed, as well as studies on analgesia and NO, the above cited reference on the reversal of erectile dysfunction by inhibitors of NO synthase suggests that the increase of cAMP by either the increase in the amount of cAMP or the reduction of cAMP degradation is pain. Will be expected to increase. In addition, there is no literature considering the effects of such complex agents on erectile dysfunction in the corpus cavernosum. Despite this, the use of combination therapies to achieve erections while removing pain is known, but this depends on additional vasodilation.
    For example, a report by B. von Heyden et al. (Journal of Urology Vol. 149: 1288 (1993)) indicates that intra- penis therapy supports the use of prostagladins (PGE1) introduced by injection into the penis. The study reports the combination of PGE1 with papaverine and phentolamine as a means of reducing pain, one of the major side effects of using prostaglandins. As noted above, with prolonged use of PGE1, pain occurred in 40-45% of patients. Although the cause of current pain is unknown, a report in the European Journal of Pharmacology (Vol 217: 225, 1992) found that activation of adenylate cyclase caused PGE2 or sympathetic nerve as a result of increased intracellular cAMP / Ca 2+ levels. It suggests that it is the cause of the increase and decrease of the nociceptor by excitatory amines. The vonHeyden study suggests that it is appropriate to reduce the level of prostaglandin use in order to reduce the likelihood of pain and the degree of pain. The simple conventional pharmacological principle that less drug produces less effect (in this case pain) applies to this concept. Reduced effects on erectile function due to reduced prostaglandins are compensated by other agents in combination therapy. There is a reference to the possibility of synergism between PGE1, paraberine and phentolamine, but any suggestion is made regarding the use of a second agent that provides a synergistic erectile response, while simultaneously reducing the pain associated with the use of prostaglandins. There is no. This technique indicates that the use of PGE1 at a concentration of 10-40 μg (previously accepted therapeutic range) causes pain.
    Hempelmann, R.G. (European Journal of Pharmacology Vol 276: 277 (1995)) addresses the question of whether vascular intestinal peptides (VIPs) and NO donors can have synergistic effects on isolated cavernous and corpus cavernosumes. . The results of this study indicate that VIP cannot induce a concentration dependent expansion reaction, whereas 3-morpholinosidnonimine molsidodomin (SIN-1) can induce complete expansion. This study demonstrates that VIP and SIN-1 have non-elevating and independent swelling effects in human penile artery and penile smooth muscle. In conclusion, this study opposes the therapeutic combination administration of these two agents.
    A study by Martinez-Pineiro, L. et al. (Journal of Urology Vol 153: 1487 (1995)) discusses intra-penis injection of vasoactive drugs, and commonly known drugs such as papaverine, phentolamine and PGE1, The therapeutic potential of the combination of these drugs is listed. In the discussion section of this paper, there is a review of the mechanism of action of pain-mediating prostaglandin-like agonists and theorizing activation through adenylyl cyclase and the effect of increasing it on cAMP levels. This is consistent with the proposed molecular basic theory of pain, as discussed above in terms of NO. However, no firm conclusions have been reached on the side effects or associated pain of such treatment.
    In conclusion, combined use has not succeeded in relieving pain associated with the use of a substance such as PGE1. Specifically, the use of prostaglandin compounds in combination with non-specific acting compounds such as papaverine and phentolamine has been shown to be associated with increased incidence of painful erectile dysfunction. In contrast, the combination therapy of the present invention results in an effective erection while reducing or completely eliminating pain.
    exam
    Two series of experiments were conducted with the results presented below. The first series (not preceded by treatment with A. PGE1) is a group of patients who have not previously used PGE1 and consequently have little chance of pain response with respect to PGE1 administration. The likelihood of pain response in this series of patients is a pain frequency per injection of 3-10% based on the literature. Although this is within the standard deviation of the experiment below, the results indicate that none of the patients experienced pain. In addition to being painless, the use of NO donors (in this case, sodium nitroprusside SNP) significantly improved the response of PGE1. Such improved response is usually associated with high doses of PGE1 and such high doses, and with pain.
    The second series of patients (preceded by treatment with B. PGE1) are part of this study and have a history associated with the use of prostaglandin treatment for penile erection. As described below, the results of this series indicated that all patients who received reduced amounts of PGE1 had reduced or no pain and improved penile erection despite a decrease in PGE1 dose.
    Common way
    First, clinical erectile dysfunction (ED) of patients with ED in the laboratory was measured. These patients were evaluated for the optimization of intra-penis injection. All people were assessed using the Queen's University Human Sexuality Group Protocol (Kingston, Ontario, Canada).
    A. No treatment of PGE1 preceded
    These patients Rigiscan TM (trade name) was adjusted to the expansion and rigidity recording apparatus. Two different drugs (PGE1 alone or in combination with sodium nitroprusside (SNP50 μg)) were injected into the penis (IC) and these erectile responses were monitored in real time. If the response to the first injection was less than 70% of maximum swelling and rigidity, the patient received only the second injection (high dose PGE1). In addition, the patient was asked to report whether or not injection-specific numbness occurred regardless of the sharp discomfort associated with the needle.
    Initial inclusion: Characterized a person with known erectile dysfunction by a 3-month history.
    except:
    1. Patients with complete dilatation in response to IC injection of the lowest dose of single PGE1 alone.
    2. Patients with no significant response at any dose (which indicates high levels of organ disease).
    3. Patients with technical problems with measurement (incomplete data).
    Two steps of measuring optimization protocol
    Step 1: (n = 9)
    First inspection-IC scanning PGE1 5 μg IC
    2nd test-IC injection PGE1 5μg + SNP 50μg
    Step 2: (n = 12)
    First test-IC injection PGE1 5 μg IC-Then (15 minutes) PGE1 15 μg IC
    Second test-IC injection PGE1 5 μg + SNP 50 μg-Then (15 minutes) PGE1 15 μg + SNP 50 μg
    result;
    Erectile reaction: Step 1 was performed to confirm the known effects of low dose PGE1 and to determine the safe range of using SNPs (Lue et al, Jounal of Urology 150: 864-867 (1993)). Four of nine patients showed insufficient response to both injections. Two of the nine experienced complete swelling at the lowest dose of PGE1 alone. Three out of nine composites showed moderate to substantial improvements. In only one patient with moderate response to low doses of PGE1 alone, there was no improvement. The data obtained from these studies confirmed that high doses of PGE1 are required to induce an erectile response, either alone or jointly, in multiple patients.
    Based on this finding, the protocol was modified to contain high dose PGE1. In the Phase 2 protocol, 4 formulations were developed: first PGE1 (5 μg in 1 ml saline), second high concentration PGE1 (15 μg in 1 ml saline), third PGE1 + SNP (5 μg + 50 μg in 1 ml saline) and fourth PGE1 + SNP (15 μg + 50 μg in 1 ml saline). In a Phase 2 study, 12 patients were measured. Complete data were available in 10 of these (see FIG. 2 where ordinates represent% rigidity units and FIG. 3). Three of these 10 responded completely to 5 + 15 μg PGE1 alone. For the remaining seven, there was a significant improvement in all patients (p <0.05) when combined with SNP. None of these patients have experienced drug-related pain from this treatment.
    B. Use of PGE1 preceded
    Patients in this study had a history of pain associated with the use of prostagladins for penile erection. As detailed below, one of the three modes of administration of NO generators was used, depending on the patient. Specifically, the patient received NO donors either through the use of nitrosprays such as Nitolingual TM or a transdermal patch delivering NO donor compounds. Received as a composite of)). The results of these treatments are detailed below.
    Case 1.
    The 55-year-old DB underwent a thorough perinectomy in October 1996. This patient received clinical injections in February 1997. After 5 μg PGE1 was injected, 5 μg PGE1 was further injected at 15 minute intervals. After the second injection, he experienced a pain in his penis for about 15 minutes. The DB used Nitrolingual TM on a general basis and required the use of Nitrospray at the time of injection of PGE1 and to record the response in his penis. He took an oral // spray of Han and reported that all of the discomfort of the penis disappeared within 2 minutes. The erection was excellent and lasting. The patient reported that this erection would be appropriate for sexual intercourse. An erection has been proven.
    Case 2.
    The 71-year-old CC underwent a strict perineal prostatectomy in January 1996, starting in October 1996 and currently using 10 μg PGE1 with pain and inadequate response at home. He met at the hospital and prescribed a transdermal patch that delivered NO donor compound at a rate of 0.2 mg / hour for 20 minutes prior to injection. 10 μg PGE1 was injected. The patient reported no pain and a good enough erection, but the couple did not want to talk anymore. An erection has been proven.
    Case 3.
    The 54-year-old GH underwent a strict perineal prostatectomy in October 1996. He reported several spontaneous and pharmacologically induced erections during the recovery period. He met in February 1997. The patient reported penile pain from home use of PGE1 without the use of 0.2 mg / hour nitropatch for 10 minutes prior to sexual reactions or injections.
    Case 4.
    JB, 54, underwent a thorough perinectomy in September 1995. He reported pain in the penis injection of PGE1. In May 1996 he used 20 μg of PGE1 with 50 μg of SNP and he reported that SNP "reduced pain".
    Case 5.
    Another 71-year-old JB had erectile dysfunction from other causes and reported pain lasting 3-4 years with injection of PGE1 in the penis. In May 1996, he used 20 μg of PGE1 with 50 μg of SNP and repeated 15 minutes later (20 μg PGE1 + 50 μg SNP) with no burning and reactions as judged by patients and experienced nurses and at least 75 % Experienced a complete erection.
    Case 6.
    TW, 58, underwent a thorough perinectomy in 1996. He reported frequent pain at midnight with PGE1. In March 1997, 10 μg of PGE1 was used with 50 μg of SNPs and repeated 15 minutes later (10 μg PGE1 + 50 μg SNP) with no burning and real efficacy, ie complete erection response.
    Concentrations of glyceryl trinitrate (a common form of NO donors derived from nitrosprays or nitropatches) are reported in the literature as 200-400 pg / ml of plasma (Sun et al, J. Clin. Pharmacol. (35) 390, 1995).
    The route of administration of PGE1 and NO donors reported here is by IC injection of prostagladin and IC injection of NO donor, or nasal spray or patch, whereas the present invention provides parenteral without harmful reactions with topical creams, active ingredients. Administration by pharmaceutically acceptable organic and inorganic carrier materials suitable for oral, oral, urethral or intranasal application is also included.
    The compositions of the present invention are administered to a subject in a suitable biologically compatible form for pharmaceutical administration in vivo. By "biologically compatible form suitable for in vivo pharmaceutical administration" is meant a form of the active compound of the invention administered in a form in which the therapeutic effect of the active compound of the invention exceeds any toxic effect. The term subject is intended to include any organism, for example a mammal, to which a response may occur. Examples of subjects include humans, dogs, cats, mice, mice and their transformed species.
    Administration of a therapeutically active amount of a therapeutic composition of the invention is defined as an amount effective in the administration and for the time period necessary to achieve the desired result. For example, the therapeutically active amount of the active compound of the present invention may vary depending on factors such as disease state, age, sex and weight of the individual and the combination of the agent of the present invention or the ability of the agent to exhibit a desirable response in the individual. can do. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered and may be reduced in proportion to that indicated by the therapeutic situation.
    The active compounds (e.g., SNPs and PGE1) may be administered in a convenient manner such as injection (subcutaneous, intravenous, penile, etc.), oral, inhalation, transdermal, rectal, urethral or penile. Depending on the route of administration, the active compound or compound may be coated with a substance to protect the compound from other natural conditions that may inactivate the enzyme, acid and compound (s) or to facilitate delivery of the compound.
    The SNP and PGE1 compositions or isolated agents can be administered to a subject with an appropriate carrier or diluent, with an inhibitor or with a suitable carrier such as liposomes. The term "pharmacologically acceptable carrier" as used herein is intended to include salts, diluents such as aqueous buffers, and solid, liquid or gaseous excipients. In order to administer the agents or agents of the invention to other parenterals, it may be necessary to administer the active ingredients of the invention together with a substance which prevents the coating or prevents inactivation. Liposomes include water / oil / water emulsions as well as conventional liposomes (Strejan et al.m J. Nerroimmunol 7:27 (1984)). The active compound (s) may also be administered parenterally or intraperitoneally. It can be prepared by dispersing in glycerol, liquid polyethylene glycol and mixtures thereof in oil or other solution. Under ordinary conditions of storage and use, these combinations may include inhibitors to prevent the growth of microorganisms, stabilizers and compounds to preserve the material properties necessary for proper delivery.
    Pharmaceutical compositions suitable for injection include sterile aqueous solutions or dispersions and sterile powders for immediate use of injectable sterile solutions or dispersions. In all cases, the composition must be sterile and fluid to the extent that it is easily injectable. The composition must be preserved so as not to be contaminated by microorganisms such as bacteria and fungi as long as it is safe under the conditions of manufacture and storage. Pharmacologically acceptable carriers may be solvents or dispersion media, such as water, ethanol, polyols (eg, glycerol, propylene glycol and liquid polyethylene glycols, etc.) and suitable mixtures thereof. Proper fluidity can be maintained, for example, by coating with a lecithin, by maintaining the required particle size in the case of dispersions and by using surfactants. For example, various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid and tiferosal, can be used to prevent the action of microorganisms. In many cases, it is preferable to include isotonic solutions, for example, sugars, mannitol, polyalcohols such as sorbitol, sodium chloride, and the like. Inclusion of absorption retardants, such as aluminum monostearate and gelatin, in the composition can be made to continuously absorb the composition to be injected.
    Sterile injectable solutions can be prepared by mixing the required amount of the active compound (eg SNP and PGE1) in a suitable solvent with one or more of the ingredients enumerated above, and if necessary, then sterilized by filtration. Generally, dispersions are prepared by mixing the active compound with a sterile excipient containing a basic dispersion medium and the other necessary ingredients enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred method of preparation is to vacuum dry and lyophilize to add any additional desired ingredients from the aforementioned sterile-filtered solutions to the active compounds of the present invention.
    As mentioned above, when the active ingredient is adequately protected, the composition can be administered orally, for example with an inert diluent or an absorbable edible carrier. As used herein, "pharmacologically acceptable carrier" means all solvents, dispersion media, coatings, antibacterial and antifungal agents. Isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmacologically active ingredients is well known in the art. As far as any conventional media or agent is concerned, their use in therapeutic compositions is contemplated, except that it is incompatible with the active compound. Active compounds complementary to the composition can also be mixed.
    It is particularly advantageous to formulate parenteral compositions in unit dosage form and in constant dosage form for ease of administration. Unit dosage form as used herein refers to physically discrete units suited in one dose for a mammalian subject; Each unit containing a predetermined active compound, calculated so as to exhibit a desired therapeutic effect, with respect to the required pharmacological carrier. Specific methods of determining the unit dosage form of the invention depend on the (a) unique properties and specific therapeutic effects desired for the active compound and (b) the inherent limitations in the technology of preparation of the active compound for the treatment of an individual.
    While the method of the present invention has been described and understood to include a combination of NO donor and PGE1, the present invention is directed to synergistic pain such as NO donor and sedatives, ibuprofen, non-steroidal anti-inflammatory drugs such as naprocene and mepanamic acid. Includes combination with other analgesics for the reduction of
    While the invention has been described in detail with reference to embodiments, it will be understood by those skilled in the art that various other changes may be made in form or detail without departing from the scope and spirit of the invention.
    All references and patents mentioned in this specification are incorporated by reference herein.
    权利要求:
    Claims (19)
    [1" claim-type="Currently amended] A method of increasing the action of cAMP in an effector system while reducing the action of cAMP in a receptive system, which consists of applying one or more various forms of NO or CO to the site where cAMP is present. .
    [2" claim-type="Currently amended] The method of claim 1, wherein said change in cAMP action is caused by application of an agent that increases cGMP.
    [3" claim-type="Currently amended] The method of claim 1, wherein said change in cAMP action is caused by inhibition of phosphodiesterase in smooth muscle and activation of cAMP phosphodiesterase in neural tissue.
    [4" claim-type="Currently amended] At an anatomical site where the nocturnal tissue is very close to one or more effector systems, the effector is reduced while the noxious tissue is reduced, consisting of altering the action of cAMP by applying one or more various forms of NO or CO to the site. How to improve your system
    [5" claim-type="Currently amended] The method of claim 4, wherein the change in cAMP is caused by the application of one or more agents that increase cGMP.
    [6" claim-type="Currently amended] 5. The method of claim 4, wherein said anatomical site is a penis.
    [7" claim-type="Currently amended] 5. The method of claim 4 wherein said anatomical site is a clitoris.
    [8" claim-type="Currently amended] A method of enhancing the erection of the penis or clitoris without minimal pain or pain, comprising using an effective amount of at least one agent that can increase the effect of cGMP as well as increase the effect of cAMP.
    [9" claim-type="Currently amended] 10. The method of claim 8, wherein the one or more agents increase the effect of cAMP on smooth muscle as well as increase the effect of cGMP in neural tissues.
    [10" claim-type="Currently amended] 10. The method of claim 8, wherein the one or more agents increase the effect of cAMP on neural tissues while inhibiting the activity of PDE3 in smooth muscle as well as increasing the effect of cAMP by stimulating adenylyl cyclase. .
    [11" claim-type="Currently amended] The method of claim 10, wherein the one or more agents produce nitrogen monoxide to inhibit PDE3 and increase the effect of cGMP.
    [12" claim-type="Currently amended] The method of claim 11, wherein the agent is glyceryl trinitrate, isosorbide 5-monitrate, isosorbide dinitrate, pentaerythritol tetranitrate, erytrityl tetranitrate, sodium nitroprusside, 3-morpholinosidronimine molsididomine, S-nitroso-N-acetylphenicamine, S-nitrosoglutathione, N-hydroxy-L-arginine, S, S-dinitrosodithiol and NO gas Characterized in that it is selected from the group consisting of:
    [13" claim-type="Currently amended] 6. The method of claim 5, wherein the agent is delivered by any route affecting the smooth muscles and nerves of the penis or clitoris.
    [14" claim-type="Currently amended] 9. The method of claim 8, wherein two agents are used and are agents that can produce NO or CO to increase the effect of cGMP.
    [15" claim-type="Currently amended] 9. The method of claim 8, wherein two agents are used, wherein one of the agents increases the effect of cAMP by stimulating adenylyl cyclase in smooth muscle and the second agent inhibits PDE3 in smooth muscle.
    [16" claim-type="Currently amended] 9. The agent according to claim 8, wherein the agent for producing NO is glyceryl trinitrate, isosorbide 5-monitrate, isosorbide dinitrate, pentaerythritol tetranitrate, erythryl tetranitrate, sodium Nitroprusside, 3-morpholinosidronimine molsididomine, S-nitroso-N-acetylphenicylamine, S-nitrosoglutathione, N-hydroxy-L-arginine, S, S-dinitrosodithiol And NO gas.
    [17" claim-type="Currently amended] 9. The method of claim 8, wherein said agent that increases or enhances the effect of cAMP is selected from the group consisting of PGE1, VIP, forstolin, acetylcholine and calcitonin related peptides.
    [18" claim-type="Currently amended] The method of claim 8, wherein the agents are delivered by any route that affects the smooth muscles and nerves of the penis or clitoris.
    [19" claim-type="Currently amended] At an anatomical site in which the nocturnal tissue is very close to one or more effector systems, the application of an agent or agents that increase or enhance the action of cAMP in the effector system and increases cGMP relative to cAMP in the noxious tissue. A method of enhancing the effector system while reducing the uptake in the receiving tissue.
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    同族专利:
    公开号 | 公开日
    EP0907366A1|1999-04-14|
    GB9608408D0|1996-06-26|
    JP2001502659A|2001-02-27|
    US6747063B2|2004-06-08|
    US20040166176A1|2004-08-26|
    AU2562797A|1997-11-12|
    WO1997039760A1|1997-10-30|
    AU719252B2|2000-05-04|
    CA2250869A1|1997-10-30|
    US20010039257A1|2001-11-08|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1996-04-23|Priority to GBGB9608408.2A
    1996-04-23|Priority to GB9608408.2
    1997-04-23|Application filed by 퀸즈 유니버시티 엣 킹스턴, 마우리스 도날드 에이치
    2000-01-25|Publication of KR20000005455A
    优先权:
    申请号 | 申请日 | 专利标题
    GBGB9608408.2A|GB9608408D0|1996-04-23|1996-04-23|Treatment of erectile dysfunction|
    GB9608408.2|1996-04-23|
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