Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2000-09-19
2001-11-13
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S179000, C514S300000, C514S318000, C514S383000
Reexamination Certificate
active
06316431
ABSTRACT:
This invention relates to the use of an aromatase inhibitor in the treatment of decreased androgen to estrogen ratio (DATER) as well as to a method for the treatment of detrusor urethral sphincter dyssynergia (DUSD) in men. Furthermore, the invention concerns a method for the in vivo investigation of the influence of a certain condition on the urinary function of male individuals using an animal model of male rodents.
BACKGROUND OF THE INVENTION
The publications and other materials used herein to illuminate the background of the invention, and in particular, cases to provide additional details respecting the practice, are incorporated by reference.
Detrusor Urethral Sphincter Dyssynergia (DUSD) and its Current Therapies
Normal voiding consists of sustained relaxation of periurethral smooth and striated muscle during sustained detrusor contraction. The anatomy of the lower urinary tract in human (a) and in rat (b) is shown in FIG.
2
. In this Figure D denote detrusor, U urethra, RB rhabdosphincter (striated urethral sphincter), PR prostate, VPR ventral prostate, LPR lateral prostate, S seminal vesicle, C coagulating gland and UR urogenital diaphragm. Inappropriate contraction or failure of complete and sustained relaxation of the urethral musculature during detrusor contraction causes voiding problems known as detrusor urethral sphincter dyssynergia. The etiopathogenesis of detrusor urethral sphincter dyssynergia is poorly understood. Three different clinical outcomes have been described: 1) bladder neck dyssynergia, 2) external sphincter pseudodyssynergia and 3) Hinman syndrome. They all are defined in this invention as detrusor urethral sphincter dyssynergia.
In the following we summarize the clinical symptoms of male functional detrusor urethral sphincter dyssynergia and its treatments taking into account especially the possible hormonal background of the symptoms.
According to the recent study (Kaplan et al. 1996) half of the men younger than 50 years old with chronic irritative and/or obstructive voiding symptoms have primary bladder outlet obstruction (bladder neck dyssynergia), and in every fourth patient, the obstruction is located to the membraneous urethra (termed as pseudodyssynergia of the external sphincter).
Bladder Neck Dyssynergia
The bladder neck dyssynergia patient is a male aged between 20 and 60 years. Bladder neck dyssynergia is usually a life-long condition. It virtually never occurs in females. At old ages, prostatic enlargement and bladder neck dyssynergia are both common conditions so their coincidence is by no means uncommon.
Symptoms of bladder neck dyssynergia are hesitance, poor urinary stream, terminal drippling and incomplete bladder emptying (Prostatic Obstruction. Pathogenesis and treatment. Ed. Christopher R. Chapple. Springer-Verlag 1994). In bladder neck dyssynergia an increased intraluminal bladder pressure in needed to empty the bladder. In the initial stages, there is no reduction in the flow rate because the maximum micturition pressure compensates for the increased outflow resistance. Patients with bladder neck dyssynergia may develop secondary detrusor instability with irritative symptoms of frequency, urgency and nocturia.
In bladder neck dyssynergia, the proximal urethra actively tightens during voiding. Smooth muscle fibers of the proximal part of the male bladder neck are morphological extensions of the cholinergically innervated detrusor fibers. The smooth muscle fibres of the distal part of the male bladder neck are morphologically distinct from the detrusor fibres and have ol-adrenergic innervation. It is possible that dysfunctional bladder neck has abnormal composition or arrangements of the smooth muscle fibers. Alterations in the contractile properties or responses of smooth muscle cannot be excluded, either. There is little evidence to support the role of smooth muscle cell hyperplasia or hypertrophy in the development of the dysfunction in men.
Bladder neck dyssynergia can be treated surgically by transecting the full thickness of the bladder neck musculature. The selective &agr;1-adrenoceptor antagonists, such as prazosin and indoramin inhibit symphatetic tone which is supposed to exacerbate the degree of obstruction of urethra through contraction of urethral smooth muscle. They used as an adjunct in the symptomatic treatment of functional urethral obstruction. Uroselective &agr;1-antagonists with high tissue selectivity for lower urinary tract smooth muscle that do not provoke hypotensive side-effects are under development.
External Sphincter Pseudodyssynergia
Increased voiding pressure or decreased flow rate are not necessarily only associated with structural or functional changes in the smooth muscle component of the lower urinary tract. Distally the prostatic urethra possesses a smooth muscle merging with the prostatic musculature. Caudal to the prostate, the urethral wall has a striated muscle layer called rhabdosphincter, urethral sphincter or external sphincter. The striated muscle extends throughout the length of the pre-penile urethra (Oelrich 1980). The proximal portion of the sphincter lies as a bundle between the base of the bladder and the proximal border of the prostate. The fibers in the central portion of the sphincter cover the lateral surface of the prostate. Caudal to the prostate, striated muscle form a horse-shoe-shaped configuration (Strasse et al. 1996). Inferior to the pelvic diaphragm, the sphincter (external sphincter) expands to fill the area between the pudendal canals (Oelrich 1980). There is no subdivision of the human urethra sphincter muscle, and no smooth muscle septa have been recognized dividing the muscle.
During the normal micturition cycle, an increase in external sphincter electromyographic activity accompanies bladder filling (continence reflex). This is followed by relaxation of the urethral sphincter and the pelvic floor muscles, which begins before or at the beginning of the detrusor contration and persists throughout the contration. External sphincter dyssynergia is defined as an inappropriate increase in striated urethral muscle (external urethral sphincter) activity during a detrusor contraction and is a well recognized cause of voiding dysfunction in patients with upper neurone lesions. This overcompensation is done to counteract the elevated bladder pressure caused by uninhibited detrusor contraction (an exaggerated continence reflex) (Rudy et al. 1988).
Most striking in all of the patients with pseudodyssynergia is the presence of contraction of the striated urethral/external sphincter during voiding (Kaplan et al. 1997). In adults, the etiology of the sphincter pseudodyssynergia may be less neurological and more functional which can be seen as narrowing of or cutting off the urinary stream during micturition (Kaplan et al. 1997). Men who have pelvic floor spasm or what Kaplan et al. (1996) term as pseudodyssynergia, may not have severely elevated voiding pressures. However, they have narrowing of the urinary stream during voiding at the level of the membraneous urethra.
Hinman Syndrome
Urodynamic investigations in children with an abnormal voiding pattern have shown dyssynergia between the detrusor and striated urethral sphincter in the absence of neurologic disease (nonneurogenic neurogenic bladder or the Hinman syndrome) (Hinman and Baumann, 1973). This appears to result from unintentional, habitual contractions of the striated urethral sphincter in response to involuntary bladder contraction to prevent urinary incontinence. This dyssynergia probably may at least partly represent a learned habit. Its more common among girls than boys. Pharmacologic manipulation of detrusor and sphincter function and biofeedback therapy have been highly successful. The relationship between the Hinman syndrome and the detrusor sphincter dyssynergia or urethral sphincter pseudodyssynergia is not known.
We suggest that the development of detrusor urethral sphincter dyssynergia is associated to estrogen or androgen/estrogen ratio. To the best of our knowledge, the hormonal etiology for the ma
Halonen Kaija
Kangas Lauri
Lammintausta Risto
Santti Risto
Streng Tomi
Henley III Raymond
Hormors Medical Oy Ltd.
Rothwell Figg Ernst & Manbeck
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