Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-04-02
2001-11-27
Celsa, Bennett (Department: 1627)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S545000, C514S754000, C514S929000, C514S968000, C424S043000, C424S400000, C424S440000, C546S050000
Reexamination Certificate
active
06323211
ABSTRACT:
FIELD OF THE INVENTION
The present invention describes methods for treating sexual dysfunctions in patients by orally administering at least one &agr;-adrenergic receptor antagonist and at least one compound that elevates endogenous nitric oxide or endothelium-derived relaxing factor in vivo. The present invention also describes orally administrable compositions comprising at least one &agr;-adrenergic receptor antagonist and at least one compound that elevates endogenous nitric oxide or endothelium-derived relaxing factor in vivo. In the present invention, the &agr;-adrenergic receptor antagonist is preferably yohimbine or phentolamine, and the compound that elevates endogenous nitric oxide or endothelium-derived relaxing factor in vivo is preferably L-arginine.
BACKGROUND OF THE INVENTION
Adequate sexual function is a complex interaction of hormonal events and psychosocial relationships. There are four stages to sexual response as described in the
International Journal of Gynecology & Obstetrics
, 51(3):265-277 (1995). The first stage of sexual response is desire. The second stage of sexual response is arousal. Both physical and emotional stimulation may lead to breast and genital vasodilation and clitoral engorgement (vasocongestion). In the female, dilation and engorgement of the blood vessels in the labia and tissue surrounding the vagina produce the “orgasmic platform,” an area at the distal third of the vagina where blood becomes sequestered. Localized perivaginal swelling and vaginal lubrication make up the changes in this stage of sexual response. Subsequently, ballooning of the proximal portion of the vagina and elevation of uterus occurs. In the male, vasodilation of the cavernosal arteries and closure of the venous channels that drain the penis produce an erection. The third stage of sexual response is orgasm, while the fourth stage is resolution. Interruption or absence of any of the stages of the sexual response cycle can result in sexual dysfunction. One study found that 35% of males and 42% of females reported some form of sexual dysfunction. Read et al,
J. Public Health Med
., 19(4):387-391 (1997).
While there are obvious differences in the sexual response between males and females, one common aspect of the sexual response is the erectile response. As described in U.S. Pat. No. 5,565,466, the disclosure of which is incorporated herein by reference in its entirety, the erectile response in both males and females is the result of engorgement of the erectile tissues of the genitalia with blood which is caused by the relaxation of smooth muscles in the arteries serving the genitalia.
In both pre-menopausal and menopausal females, sexual dysfunction can include, for example, sexual pain disorders, sexual desire disorders, sexual arousal dysfunction, orgasmic dysfunction, dyspareunia, and vaginismus. Sexual dysfunction can be caused, for example, by pregnancy, menopause, cancer, pelvic surgery, chronic medical illness or medications.
In males, some pharmacological methods of treatment are available, however, such methods have not proven to be highly satisfactory or without potentially severe side-effects. Papaverine is now widely used treat impotence. Papaverine is generally effective in cases where the dysfunction is psychogenic or neurogenic and where severe atherosclerosis is not involved. Injection of papaverine, a smooth muscle relaxant, or phenoxybenzamine, a non-specific antagonist and hypotensive, into a corpus cavernosum has been found to cause an erection sufficient for vaginal penetration, however, these treatments are not without the serious and often painful side effect of priapism. Also, in cases where severe atherosclerosis is not a cause of the dysfunction, intracavernosal injection of phentolamine, an &agr;-adrenergic antagonist, is used. As an alternative or, in some cases, as an adjunct to &agr;-adrenergic blockade, prostaglandin E
1
(PGE
1
) has been administered via intracavernosal injection. A major side effect frequently associated with intracorprally delivered PGE
1
is penile pain and burning.
There is a need in the art for new and improved treatments of male and female sexual dysfunctions, particularly treatments that do not have the undesirable side effects of those agents currently used. The present invention is directed to these, as well as other, important ends.
SUMMARY OF THE INVENTION
The present invention provides methods for preventing and/or treating sexual dysfunctions and/or enhancing sexual responses in patients, including males and females, by administering to a patient in need thereof a therapeutically effective amount of at least one &agr;-adrenergic receptor antagonist and at least one compound that elevates levels of endogenous nitric oxide or endothelium-derived relaxing factor (EDRF) in vivo. Preferably, the &agr;-adrenergic receptor antagonist is yohimbine or phentolamine. Preferably, the compound that elevates levels of endogenous nitric oxide or EDRF in vivo is L-arginine. In the methods of the present invention, the compounds may be administered separately or as components of the same composition. The compounds and/or compositions are preferably administered from about 1 minute to about 120 minutes prior to sexual activity or intercourse in order to prevent and/or treat sexual dysfunctions and/or to enhance sexual responses in a patient.
In another embodiment, the present invention provides orally administrable compositions comprising a therapeutically effective amount of at least one &agr;-adrenergic receptor antagonist, and at least one compound that elevates levels of endogenous nitric oxide or endothelium-derived relaxing factor (EDRF) in vivo. The invention also provides compositions comprising one or more of such compounds in a pharmaceutically acceptable carrier. The &agr;-adrenergic receptor antagonist is preferably yohimbine or phentolamine. The compound that elevates levels of endogenous nitric oxide or EDRF in vivo is preferably L-arginine.
These and other aspects of the present invention are described in detail herein.
DETAILED DESCRIPTION OF THE INVENTION
The following definitions may be used throughout the specification.
“Patient” refers to animals, preferably mammals, more preferably humans.
“&agr;-adrenergic receptor antagonist” refers to any compound that acts as an antagonist to the &agr;-adrenergic receptor.
“L-arginine” refers to the naturally occurring form of arginine.
“Sexual dysfunction” refers to any sexual dysfunction in a patient, including males and females. Sexual dysfunctions may include, for example, sexual desire disorders, sexual arousal disorders, orgasmic disorders and sexual pain disorders. Female sexual dysfunctions refer to any female sexual dysfunctions including, for example, sexual desire dysfunctions, sexual arousal dysfunctions, orgasmic dysfunctions, sexual pain disorders, dyspareunia, and vaginismus. The female may be pre-menopausal or menopausal. Male sexual dysfunctions refer to any male sexual dysfunctions including, for example, male erectile dysfunction and impotence.
“Pharmaceutically acceptable salts” refer to neutral and acid salts. Pharmaceutically acceptable salts include, for example, those formed with free amino groups, such as those derived from hydrochloric, hydrobromic, hydroiodide, phosphoric, sulfuric, acetic, citric, benzoic, fumaric, glutamic, aspartic, lactic, malic, maleic, succinic, tartaric, p-toluenesulfonic, methanesulfonic acids, gluconic acid, and the like, and those formed with free carboxyl groups, such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxides, isopropylamine, triethylamine, 2-ethylamino ethanol, histidine, procaine and the like.
The present invention is directed to the treatment and/or prevention of sexual dysfunctions in patients, including males and females, by administering the compounds and compositions described herein. The present invention is also directed to enhancing sexual responses in patients, including males and females, by administering the compounds and/or compositions described herein.
Ni
de Tejada Inigo Saenz
Garvey David S.
Schroeder Joseph D.
Celsa Bennett
Hale and Dorr LLP
NitroMed Inc.
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