Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-12-17
2001-09-18
Travers, Russell (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06291471
ABSTRACT:
TECHNICAL FIELD
This invention relates to medical methods of treatment. More particularly, the invention concerns the use of apomorphine for the treatment of organic erectile dysfunction in males, particularly vasculogenic erectile dysfunction.
BACKGROUND OF THE INVENTION
In the medical literature the less precise term, “impotence” has been replaced by the term “erectile dysfunction.” This term has been defined by the National Institutes of Health as the inability of the male to attain and maintain erection of the penis sufficient to permit satisfactory sexual intercourse.
J. Am. Med. Assoc
., 270(1):83-90 (1993). Because adequate arterial blood supply is critical for erection, any disorder that impairs blood flow may be implicated in the etiology of erectile failure. Erectile dysfunction affects millions of men and, although generally regarded as a benign disorder, has a profound impact on their quality of life. It is recognized, however, that in many men psychological desire, orgasmic capacity, and ejaculatory capacity are intact even in the presence of erectile dysfunction.
Etiological factors for erectile disorders have been categorized as psychogenic or organic in origin. Organic factors include those of a neurogenic origin and those of a vasculogenic origin. Neurogenic factors include, for example, lesions of the somatic nervous pathways which may impair reflexogenic erections and interrupt tactile sensations needed to maintain erections, and spinal cord lesions which, depending upon their location and severity, may produce varying degrees of erectile failure.
Psychogenic factors for erectile dysfunction include such processes as depression, anxiety, and relationship problems which can impair erectile functioning by reducing erotic focus or otherwise reducing awareness of sensory experience. This may lead to an inability to initiate or maintain an erection.
Vasculogenic risk factors include factors which affect blood flow and include cigarette smoking, diabetes mellitus, hypertension, vascular disease, high levels of serum cholesterol, low levels of high-density lipoprotein (HDL), and other chronic disease conditions such as arthritis. The Massachusetts Male Aging Study (MMAS, as reported by H. A. Feldman, et al.,
J. Urol
., 151: 54-61 (1994) found, for example, that the age-adjusted probability of complete erectile dysfunction was three times greater in subjects reporting treated diabetes than in those without diabetes. While there is some disagreement as to which of the many aspects of diabetes is the direct cause of erectile dysfunction, vascular disease is most frequently cited.
The MMAS also found a significant correlation between erectile dysfunction and heart disease with two of its associated risk factors, hypertension and low serum high density lipoprotein (HDL). It has been reported that 8-10% of all untreated hypertensive patients are impotent at the time they are diagnosed with hypertension. The association of erectile dysfunction with vascular disease in the literature is strong, with impairments in the hemodynamics of erection demonstrated in patients with myocardial infarction, coronary bypass surgery, cerebrovascular accidents, and peripheral vascular disease. The MMAS also found cigarette smoking to be an independent risk factor for vasculogenic erectile dysfunction, with cigarette smoking found to exacerbate the risk of erectile dysfunction associated with cardiovascular diseases.
The treatment of erectile dysfunction varies, depending upon the root causes of the condition in a particular patient. The mode of treatment may involve the use psychotherapeutic, surgical, mechanical, or pharmacotherapeutic methodology. Psychotherapy and/or behavioral therapy are often useful for some patients with erectile dysfunction with no obvious organic cause (psychogenic). Venous ligation is effective in the treatment of patients who have difficulty maintaining an erection due to demonstrated venous leakage from the
corpus cavernosa
. Vacuum constriction devices are sometimes effective in generating and maintaining erections in patients with erectile dysfunction, and semi-rigid, malleable, or inflatable penile prostheses are available for patients who fail or refuse other forms of therapy.
Pharmacologic agents which have been used in the treatment of erectile dysfunction include vasodilators which are injected directly into the body of the penis, as well as orally administered agents. The most effective and well-studied of the injectable vasodilators are papaverine hydrochloride, phentolamine, and alprostadil, used singly or in combination. However, use of penile vasodilators can be problematic in patients who cannot tolerate transient hypotension. Orally administered agents include yohimbine, bromocriptine, fluoxetine, trazadone, trental, sildenafil, phentolamine, and extracts of
ginkgoacea biloba.
U.S. Pat. No. 5,770,606 discloses the sub-lingual administration of apomorphine for the treatment of psychogenic erectile dysfunction in males. Apomorphine, a derivative of morphine, was first evaluated for use as a pharmacologic agent as an emetic in 1869. In the first half of the 20
th
century, apomorphine was used as a sedative for psychiatric disturbances and as a behavior-altering agent for alcoholics and addicts. By 1967, the dopaminergic effects of apomorphine were realized, and the compound underwent intensive evaluation for the treatment of Parkinsonism. Since that time, apomorphine has been classified as a selective dopamine receptor agonist that stimulates the central nervous system producing an arousal response manifested by yawning and penile erection in animals and man.
SUMMARY OF THE INVENTION
It has been found, in accordance with the present invention that organic erectile dysfunction in a male can be effectively treated or ameliorated by administering to a male in need of such treatment a therapeutically effective amount of apomorphine or a pharmaceutically acceptable salt, ester, or pro-drug thereof. In particular, organic erectile dysfunction having a vasculogenic origin is effectively treated by oral administration of apomorphine.
In accordance with the invention, apomorphine is administered in an amount sufficient to produce an effective penile erection, but insufficient to induce nausea, typically in doses which result in an amount sufficient to establish plasma concentration levels of apomorphine preferably ranging up to about 5.5 nanograms/mL. The compound or one of its appropriate salts or pro-drugs may be administered alone or, if needed at the higher end of the dose range, in combination with an anti-emetic agent.
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Lue, T. F. “Impotence: a patient's goal-directed approach to treatment.”World Journal of Urology, vol. 8, 1990, pp. 67-74.
NIH Consensus Development Panel on Impotence, “Impotence.”The Journal of the American Medical Association, vol. 270(1), Jul. 1993, pp. 83-90.
Feldman, H. A., et al. “Impotence and its Medical and Psychosocial Correlates: Results of the Massachusetts Male Aging Study.”The Journal of Urology, vol. 151, Jan. 1994, pp. 54-61.
Sachs, B. D., et al. “Effects of Copulation on Apomorphine-Induced Erection in Rats.”Pharmacology Biochemistry and Behavior, vol. 48(2), 1994, pp. 423-428.
Heaton, J. P. W., et al., “Recovery of Erectile Function by the Oral Administration of Apomorphine.”Urology, vol. 45(2), Feb. 1995, pp. 200-206.
Levine, L. A., et al. “Use of Nocturnal Penile Tumescence and Rigidity in the Evaluation of Male Erectile Dysfuncti
Kling Karen
Perdok Renee J.
Ruff Dustin D.
ABB Holdings, Inc.
McNeil James D.
Travers Russell
LandOfFree
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