Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-10-19
2003-09-02
Cook, Rebecca (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06613768
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to highly selective phosphodiesterase (PDE) enzyme inhibitors and to their use to treat female arousal disorder (FAD), also known as female sexual arousal disorder (FSAD). In particular, the present invention relates to potent inhibitors of cyclic guanosine 3′,5′-monophosphate specific phosphodiesterase type 5 (PDE5) that, when administered as a pharmaceutical product, are useful for the treatment of FAD.
BACKGROUND OF THE INVENTION
Female sexual dysfunction (FSD) is a highly prevalent condition (R. T. Micheal et al.,
Sex in America
, Little Brown, Boston, Mass. (1994)). However, in contrast to the overwhelming interest in treatment of male erectile dysfunction (MED) (Feldman et al. 1994, NIH Consensus Development Panel on Impotence 1993, Rosen et al. 1997, Sildenafil Study Group 1998), relatively little attention has been paid to sexual problems in women. There are few studies of the physiological process of the female sexual response, and there are few effective treatments available to women for sexual problems. Furthermore, a barrier to research and development in this area has been the lack of established diagnostic classifications, or of established endpoints, for testing new drugs in clinical trials for the treatment of FSD.
FSD has been used as a “catchall” phrase to include a variety of sexual disorders in woman including sexual desire disorders, sexual arousal disorders, orgasmic disorders, sexual pain disorders, vaginismus, dyspareunia, trauma from sexual contact, sexual inhibition, sexual panic disorders, childhood sexual abuse, and sexual addiction or compulsive behavior. From the multitude of disorders, The American Psychiatric Association,
Diagnostic and Statistical Manual, Mental Disorders, Ed.
3, Washington, D.C., APA (1980) and the International Classification of Diseases (World Health Organization) have identified four major categories of female sexual dysfunction: (1) sexual desire disorders, (2) sexual arousal disorders, (3) orgasmic disorders, and (4) sexual pain disorders. Each of these categories can be further sub-typed as follows: lifelong versus acquired type; generalized versus situational type; etiologic classification (e.g., organic, psychogenic, mixed, unknown).
Sexual desire disorders are defined by the following two diagnoses. Hypoactive Sexual Desire Disorder (HSDD) is the persistent or recurrent deficiency (or absence) of sexual fantasies/thoughts and/or desire for, or receptivity to, sexual activity, which causes personal distress. Sexual Aversion Disorder is the persistent or recurrent phobic aversion to, and avoidance of, sexual contact with a sexual partner, which causes personal distress.
Sexual arousal disorders are defined as a recurrent inability to attain, or maintain until completion of sexual activity, an adequate lubrication/swelling response of sexual excitement. The arousal response consists of vasocongestion in the pelvis, vaginal lubrication, and expansion and swelling of external genitalia. The disturbance must cause marked distress or interpersonal difficulty.
Orgasmic disorders are defined as the persistent or recurrent difficulty, delay in, or absence of, attaining orgasm following sufficient sexual stimulation and arousal, which causes personal distress.
Sexual pain disorders are defined by the following three diagnoses. Dyspareunia is a recurrent or persistent genital pain associated with sexual intercourse. Vaginismus is a recurrent or persistent involuntary spasm of the musculature of the outer third of the vagina that interferes with vaginal penetration, which causes personal distress. Noncoital Sexual Pain Disorder is a recurrent or persistent genital pain induced by noncoital sexual stimulation.
Unfortunately, use of the term “female sexual dysfunction” as a catchall phrase to broadly encompass all disorders fails to distinguish the significant clinical and physiological differences between these disorders, and offers little guidance to the attending physician with respect to how to properly diagnose and prescribe pharmacological treatment. Because pharmacological treatment is not uniformly effective against all varieties of female sexual dysfunction, there remains a need in the art to identify which pharmacological therapy is useful to treat which sexual disorder.
Place et al. U.S. Pat. No. 5,877,216 discloses a method of treating sexual dysfunction in a female individual by administering a pharmaceutical formulation containing a selected vasodilating agent to the vagina and/or vulvar area of the individual undergoing treatment. The application is directed to prostaglandins, but additional vasodilation agents that are useful in conjunction with the invention are disclosed and include, inter alia, phosphodiesterase inhibitors. Phosphodiesterase inhibitors are not further defined. Neither PDE5 inhibitors or their use to treat female arousal disorder are disclosed.
EP 0 702 555 describes the method of treating male erectile dysfunction with a PDE inhibitor and particularly a PDE5 inhibitor. The patent application further suggests that a PDE inhibitor may be used for female sexual dysfunction, particularly orgasmic dysfunction related to clitoral disturbances. Neither PDE inhibitor, PDE5 inhibitor, nor female sexual dysfunction are defined further except by reference to compounds specifically disclosed and referenced to orgasmic dysfunction.
Sildenafil citrate (sildenafil, sold under the trademark VIAGRA®), is a known PDE5 inhibitor, and has been shown to facilitate erectile function in men suffering from MED. In particular, sildenafil amplifies the effect of central and peripheral physiologic signals resulting in cyclic guanosine monophosphate (cGMP) mediation of corpus cavernosum smooth muscle relaxation, leading in turn to vasodilation and blood pooling which produces an erection. While there are obvious external anatomical differences between male and female external genitalia, there also is a recognized tissue homology. In addition, there is accumulating evidence of analogous physiological responses (for example, relaxation of clitoral corpus cavernosum and genital vasodilation, K. Park et al.,
Biochem. Biophys. Res. Commun.,
249(3):612-617 (1998)), in female sexual tissue. However, the clinical significance of a response in female sexual tissue, and what, if any, disorder this response correlates to has not been disclosed.
While sildenafil is approved for use in males, several publications have referenced clinical studies in women. M. Fava et al., in
Psychother. Psychosom.,
67(6): 328-31 (1998), studied the effects of sildenafil on antidepressant-induced sexual dysfunction in 14 depressed patients (9 men and 5 women). Antidepressant-induced sexual dysfunction is generally characterized by a lack of desire (sexual desire disorder) and delayed orgasm and anorgasmia (orgasmic disorder), but also may include arousal difficulties, H. G. Nurnberg et al.,
J. Clin. Psychiatry,
60(1), 33-35 (1999). The study reports a statistically significant improvement in all domains of sexual functioning with a 69% rate of patients reporting improvement. However, the study fails to indicate the response by gender-(9 out of 14 patients were men). In addition, the study was not placebo controlled, and fails to correct the data for a placebo effect. The authors could not “rule out the possibility that clinical improvements in sexual functioning in our patients may be the result of nonspecific placebo-like effects.” These shortcomings in the study leave a person skilled in the art unable to draw conclusions with respect to the efficacy of using sildenafil in treating sexual desire disorder and anorgasmia, and the study offers no motivation to study its usefulness to treat female arousal disorder.
Kaplan et al., in
Urology
53(3):481-6 (1999), studied the safety and efficacy of sildenafil in postmenopausal woman with self-described sexual dysfunction. The form of sexual dysfunction being treated was not further defined or characterized. Sildenafil was studied in thi
Allemeier Lora L.
Brashear Diane L.
Ferguson Kenneth M.
Pullman William E.
Cook Rebecca
Lilly ICOS LLC
Marshall Gerstein & Borun
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