Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-01-10
2003-01-28
Moezie, Minna (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S415000, C514S410000, C514S429000, C514S428000
Reexamination Certificate
active
06512002
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to compositions and methods for treating conditions responsive to testosterone administration including male subject sexual dysfunction, lowered libido in female subjects including post-menopausal women and timidity in female subjects including post-menopausal women. The compositions and methods utilize estrogen agonist/antagonist compounds.
BACKGROUND OF THE INVENTION
Testosterone, the principal androgen, is synthesized in the testis, the ovary, and the adrenal cortex. In the circulation, testosterone serves as a prohormone for the formation of two classes of steroids: 5&agr;-reduced androgens, which act as the intracellular mediators of most androgen action, and estrogens, which enhance some androgenic effects and block others. Thus the net effect of the action of endogenous androgens is the sum of the effects of the secreted hormone (testosterone), its 5&agr;-reduced metabolite (dihydrotestosterone, and its estrogenic derivative (estradiol). Adequate amounts of these hormones are required for proper physical development and physiological homeostasis. When diminished or absent from the body, pathological conditions can arise in the body due to a testosterone deficiency which are treatable by testosterone replacement. Additional conditions can be treated or ameliorated through the supplementation of endogenous testosterone.
Conditions responsive to testosterone elevation may arise in women as a result of menopause. Menopause occurs naturally at an average age of 50 to 51 years in the USA. As ovaries age, response to pituitary gonadotropins (follicle-stimulating hormone [FSH] and luteinizing hormone [LH]) decreases, initially resulting in shorter follicular phases (thus, shorter menstrual cycles), fewer ovulations, decreased progesterone production, and more irregularity in cycles. Eventually, the follicle fails to respond and does not produce estrogen. The transitional phase, during which a woman passes out of the reproductive stage, begins before menopause. It is termed the climacteric or perimenopause, although many persons refer to it as menopause.
Premature menopause refers to ovarian failure of unknown cause that occurs before age 40. It may be associated with smoking, living at high altitude, or poor nutritional status. Artificial menopause may result from oophorectomy, chemotherapy, radiation of the pelvis, or any process that impairs ovarian blood supply.
Symptoms of the climacteric range from nonexistent to severe. Hot flushes (flashes) and sweating secondary to vasomotor instability affect 75% of women. Most women have hot flushes for more than 1 year, and 25 to 50% for more than 5 years. The woman feels warm or hot and may perspire, sometimes profusely. The skin, especially of the head and neck, becomes red and warm. The flush, which may last from 30 sec to 5 min, may be followed by chills. Vasomotor symptoms of the hot flush coincide with the onset of LH pulses, but not every increase in LH is associated with a hot flush, suggesting that hypothalamic control of LH pulses is independent of that of flushes. This independence is confirmed by the occurrence of hot flushes in women who have had pituitary failure and do not secrete LH and/or FSH.
Psychologic and emotional symptoms—including fatigue, irritability, insomnia, inability to concentrate, depression, memory loss, headache, anxiety, and nervousness and timidity can occur. Sleep disruption by recurrent hot flushes contributes to fatigue and irritability. Intermittent dizziness, paresthesias, palpitations, and tachycardia may also occur. Nausea, constipation, diarrhea, arthralgia, myalgia, cold hands and feet, and weight gain are also common.
The large reduction in estrogen leads to profound changes in the lower genital tract; eg, the vaginal mucosa and vulvar skin become thinner, the normal bacterial flora changes, and the labia minora, clitoris, uterus, and ovaries decrease in size. Inflammation of the vaginal mucosa (atrophic vaginitis) can cause the mucosa to have a strawberry appearance and can lead to urinary frequency and urgency, vaginal dryness, and dyspareunia. Women tend to lose pelvic muscle tone and to develop urinary incontinence, cystitis, and vaginitis.
In men, conditions responsive to testosterone elevation may be caused by primary hypogonadism (congenital or acquired) including testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, or orchidectomy, Klinefelter's syndrome, chemotherapy, or toxic damage from alcohol or heavy metals. Also, in men, these conditions may be caused by secondary, i.e., hypogonadotropic, hypogonadism (congenital or acquired)—idiopathic gonadotropin or luteinizing hormone-releasing hormone (LHRH) deficiency, or pituitary-hypothalamic injury from tumors, trauma, or radiation. These men have low serum testosterone concentrations without associated elevation in gonadotropins.
The sexual response cycle is mediated by a delicate, balanced interplay between the sympathetic and parasympathetic nervous systems. Vasocongestion is largely mediated by parasympathetic (cholinergic) outflow; orgasm is predominantly sympathetic (adrenergic). Ejaculation is almost entirely sympathetic; emission involves sympathetic and parasympathetic stimulation. These responses are easily inhibited by cortical influences or by impaired hormonal, neural, or vascular mechanisms. &bgr;-Adrenergic blockers may desynchronize emission, ejaculation, and perineal muscle contractions during orgasm, and serotonin agonists frequently interfere with desire and orgasm.
Disorders of sexual response may involve one or more of the cycle's phases. Generally, both the subjective components of desire, arousal, and pleasure and the objective components of performance, vasocongestion, and orgasm are disturbed, although any may be affected independently.
Sexual dysfunctions may be lifelong (no effective performance ever, generally due to intrapsychic conflicts) or acquired (after a period of normal function); generalized or limited to certain situations or certain partners; and total or partial.
Penile erection is initiated by neuropsychologic stimuli that ultimately produce vasodilation of the sinusoidal spaces and arteries within the paired corpora cavernosa. Erection is normally preceded by sexual desire (or libido), which is regulated in part by androgen-dependent psychological factors. Although nocturnal and diurnal spontaneous erections are suppressed in men with androgen deficiency, erections may continue for long periods in response to erotic stimuli. Thus, continuing action of testicular androgens appears to be required for normal libido but not for the erectile mechanism itself.
The penis is innervated by sympathetic, parasympathetic, and somatic fibers. Somatic fibers in the dorsal nerve of the penis form the afferent limb of the erectile reflex by transmitting sensory impulses from the penile skin and glans to the S2-S4 dorsal root ganglia via the pudendal nerve. Unlike the corpuscular-type endings in the penile shaft skin, most afferents in the glans terminate in free nerve endings. The efferent limb begins with parasympathetic preganglionic fibers from S2-S4 that pass in the pelvic nerves to the pelvic plexus. Sympathetic fibers emerging from the intermediolateral gray areas of T11-L2 travel through the paravertebral sympathetic chain ganglia, superior hypogastric plexus, and hypogastric nerves to enter the pelvic plexus along with parasympathetic fibers. Somatic efferent fibers from S3-S4 that travel in the pudendal nerve to the ischiocavernosus and bulbocavernosus muscles and postganglionic sympathetic fibers that innervate the smooth muscle of the epididymis, vas deferens, seminal vesicle, and internal sphincter of the bladder mediate rhythmic contraction of these structures at the time of ejaculation.
Autonomic nerve impulses, integrated in the pelvic plexus, project to the penis through the cavernous nerves that course along the posterolateral aspect of the prostate before penetrating t
Day Wesley W.
Lee Andrew G.
Thompson David D.
Benson Gregg C.
Crissey Todd M.
Jiang S.
Moezie Minna
Pfizer Inc.
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