Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
1998-10-23
2004-06-08
Wang, Shengjun (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C514S002600, C514S012200, C514S562000, C514S645000
Reexamination Certificate
active
06747063
ABSTRACT:
FIELD OF THE INVENTION
The field of 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 enhanced capacity for corpus cavernosal smooth muscle relaxation (penile erection).
BACKGROUND OF THE INVENTION
Erectile dysfunction (ED) is a significant clinical problem which occurs in up to thirty percent of males in North America. Causes of impotence are usually divided into two nonexclusive categories, namely, organic and psychological. Organic aspects of ED are typically caused by underlying vascular disease such as that associated with hypertension or diabetes mellitus, can be caused by prescription medications and may include psychiatric disease such as depression. Psychological factors include fear, performance anxiety and interpersonal conflict. ED impairs sexual performance, diminishes self-esteem and disrupts personal relationships (Padma-Nathan, et al NEJM, Vol. 336 (1):1, 1997).
The human male penis is composed of erectile tissue called the corpus cavernosum and corpus spongiosum. The corpus cavernosum is comprised of two segments or erectile bodies each located adjacent to the urethra (or the corpus spongiosum). 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 very engorged by blood when dilated (relaxed). The dilation of these tissues contributes directly to penile erection.
The stimulus for a physiological erection originates in the central nervous system. A fully functional natural penile erection requires co-ordinated change in output from various levels of the central nervous system and at least three sets of peripheral nerves (thoracolumbar sympathetic, sacral parasympathetic, and pelvic somatic). At the level of penile tissue, localization of sympathetic and parasympathetic as well as non-adrenergic, non-cholinergic nerve terminals has indicated the potential involvement of numerous neurotransmitter systems. A penile erection is known to be dependent upon the balance and integration between structural (vascular and extracellular matrix) and functional control systems (neural, local factors and humoral/endocrine). The nature of the balance between these contributing influences is ultimately expressed as vasodilation and penile tumescence, as long as there is an adequate level of systemic blood pressure and an appropriate hormonal milieu. The penile vascular components that have a significant role in regulating erectile function are the pudendal arterial system, the cavernous arteries, the corpora cavernosa and the corpus spongiosum and glans.
It is well established that an erection requires a neurally mediated (autonomic) vasodilation of both the penile arterial blood vessels and the trabecular meshwork. The combined dilatation facilitates an initial rapid increase in arterial inflow into the cavernous bodies of the penis, promoting tumescence. This is followed by a phase of decreasing inflow as the corporal tissue expands and compresses sub-tunical veins. This is described as the “veno-occlusive mechanism”, and this imposes a dramatic increase in inflow resistance which is required to achieve penile rigidity. Conversely, detumescence is likely mediated, at least in part, by activation of the sympathetic nervous system as well as removal of active vasodilator tone. In addition, it may involve changes in local systems.
One of the widely accepted interventions used in the diagnosis and pharmacological management of erectile dysfunction involves direct injection of a wide range of vasoactive substances into the corpus cavernosum (penis) for the purposes of producing an erection (intra cavernosal “IC” injections). Newer strategies involve the delivery of a similar range of drugs to the urethra (then 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 drug-induced pain and priapism (i.e., erections of inappropriate overlong duration) (Linet et al, NEJM, Vol. 334:873 (1996)). It is now known and has been documented in the literature that a single use of prostaglandin E1 (PGE1) produces a pain response in about 3 to 10 percent of individuals using this therapy. However, it also known that over time the repeated use of PGE1 is associated with a continuing incidence of pain. This is such that 40 to 45 percent of patients using PGE1 multiple times will report a pain response with use (Linet et al, NEJM, Vol 334 (14) 873 (1996)). When such patients use PGE1 for a prolonged period of time, they expect that they may experience pain and this becomes a serious problem which may result in decreased use of PGE1 or switching to an alternative therapy. Alternatives currently include surgical intervention (destructive and irreversible, with a success rate between 31 to 80 percent); vacuum devices (moderate efficacy, may be difficult for some men to use and may cause penile trauma); and oral medications (unproven efficacy). Transurethral administration of PGE1 or other vasoactive agents is another alternative approach to injection therapy, although it has resulted in report of penile pain in 35.7 percent of men who attended for clinic testing (Padma-Nathan et al, NEJM, Vol. 336(1): 1 (1997)). At present it is our understanding only two products are approved by the United States FDA for the treatment of ED: intracavernosal injection using PGE1 (Caverject, Upjohn Pharmaceutical; Virilan, Schwarz Pharma) and intraurethral PGE1 (MUSE, Vivus Inc. Menlo Park, Calif.). Thus there is a need to provide a method or therapy for inducing effective erections (and avoid priapism) while reducing or entirely avoiding pain.
SUMMARY OF INVENTION
The present invention is a therapy in which the combination of actions of an agent or agents induce effective erections (and avoid priapism) while reducing or entirely avoiding pain.
According to one aspect of the present invention there is provided a method of augmenting the actions of cyclic adenosine monophosphate (cAMP) in an effector system while reducing cAMP action in a nociceptive system which method comprises application of one or more of the various forms of NO, or CO, to a site wherein the said cAMP exists.
According to another aspect of the present invention, a method is provided wherein alteration of the actions of cAMP is caused by application of an agent which increases cyclic guanosine monophosphate (cGMP).
According to another aspect of the present invention, a method is provided wherein alteration of the actions of cAMP is caused by application of an agent which inhibits phosphodiesterase.
In yet a further aspect of the present invention there is provided, in an anatomical site where nociceptive tissue is in close proximity to one or more effector systems, a method for enhancing said effector system while reducing nociception in said nociceptive tissue comprising modifying the actions of cAMP at said site by application of one or more of the various forms of NO or CO, or comprising application of an agent or agents that potentiate or augment the action of cAMP in said effector systems and in said nociceptive tissue, causing an increase of cGMP relative to cAMP, which would include an overall reduction in cAMP but with relatively more cGMP. The penis and clitoris are examples of such anatomical sites.
According to one aspect of the present invention there is provided a method of enhancing penile erection with minimal or no pain by use of one or more agents that can augment or potentiate the effect of cAMP as well as augment or potentiate the effect of cGMP in both smooth muscle and nerves, irrespective of whether the effect is mediated by changes in the adenylyl or guanylyl cyclase systems or by direct action of NO or CO, or the cy
Adams Michael A.
Heaton Jeremy P. W.
Maurice Donald H.
Cellegy Pharmaceuticals Inc.
Towsend and Towsend and Crew LLP
Wang Shengjun
LandOfFree
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