Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2000-09-08
2003-11-04
Killos, Paul J. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C560S121000, C562S503000
Reexamination Certificate
active
06642274
ABSTRACT:
FIELD OF THE INVENTION
The present invention generally relates to novel compositions, methods, devices and kits for the prevention and/or treatment of prostate disorders in mammals. The present invention also generally relates to devices for the administration of therapeutic compounds to mucosal membranes in the lower urinary tract of mammals.
BACKGROUND OF THE INVENTION
Diseases of the prostate are common maladies of male mammals, especially men. They include benign prostatic hypertrophy (BPH), carcinoma of the prostate (CaP), prostadynia, prostatitis, and chronic prostatitis.
The steadily increasing age of the world's population is a testament to the success of modem medicine and preventive care. However, this success has brought with it the problem of a greater number of men suffering from BPH, CaP and other prostate disorders.
The incidence of BPH increases steadily with age and is a nearly universal autopsy diagnosis of men in the 8
th
and 9
th
decades of their life (HA Guess, “Epidemiology and natural history of benign prostatic hyperplasia,” Urol Clin North Am. 1995; 22:247-261). At least 75% of men over the age of 70 have symptoms consistent with BPH and about 30% of men may have surgery to treat BPH during their lifetime. The Baltimore Longitudinal Study of Aging found that almost 60% of men aged 60 years or older were given a clinical diagnosis of BPH (HM Arrighi et al, “Natural history of benign prostatic hyperplasia and risk of prostatectomy. The Baltimore Longitudinal Study of Aging,” Urology 1991; 38 Suppl. 1:4-8). Other mammals that are known to exhibit a high incidence of BPH include dogs and Syrian Hamsters.
Carcinoma of the prostate is now the most common malignancy of men and shows the same pattern of increasing incidence with age as does BPH (SL Parker et al, “Cancer statistics,” CA Cancer J Clin 1997; 45:5-27). Indeed, it has been said that every man would develop carcinoma of the prostate (CaP) if he lived long enough.
The bladder serves as a storage vessel for urine produced by the kidneys until the mammal desires to eliminate the urine by voiding. The urethra is a tube or conduit through which urine flows from the bladder to the exterior of the mammal. In man, the urethra is composed of three main divisions—the prostatic, the membranous and the penile segments (FIG.
1
).
The prostate gland encases the urethra as it exits the bladder. This anatomical arrangement in which the urethra is completely surrounded by the prostate makes it susceptible to compression by the prostate. Any encroachment upon the lumen of the prostatic urethra will result in obstruction to the flow of urine.
BPH causes obstruction to the flow of urine by two major mechanisms that are distinct components—a static (fixed) component due to the hypertrophied prostate tissue and a dynamic component due to excessive tone in the smooth muscle tissues of the prostate. Both of these mechanisms cause compression and obstruction of the urinary outflow tract. The pathophysiology of BPH involves hypertrophy of the glandular and stromal tissue of the peripheral zone of the prostate and the periurethral area that surrounds the urethra (see
FIG. 2
) leading to narrowing of the lumen and mechanical obstruction of the urinary outflow tract. Pathology findings on prostate tissue from patients with BPH include fibrosis and hyperplasia of the musculature and gland structure of the prostate.
Patients with BPH commonly complain of symptoms that include difficulty initiating urination (hesitancy), difficulty terminating urination (dribbling), frequent urination secondary to an inability to completely empty the bladder of urine (frequency) and having to awaken in the night to empty the bladder (nocturia). Since no methods are known to prevent or cure BPH, the primary focus of treating BPH is to alleviate these complaints and thereby improve the patient's quality of life.
Two measures of the degree of outflow tract obstruction that are commonly followed in studies of patients with BPH are the subjective complaints of BPH symptoms and measures of the ability to empty the bladder of urine (urodynamics). Urodynamics studies consist of measuring the rate of urine flow and the quantity of urine produced as the patient urinates into a container placed on an electronic scale. A graph of urine flow versus time is produced and the patient's urine flow measurements may then be compared to population derived average urine flow measurements. More complex urodynamics studies measure pressures produced by contraction of the bladder muscles during urination. One measure of the degree of urinary tract obstruction is the maximum or peak urinary flow rate as measured by urodynamics studies.
FIG. 3
shows typical urodynamics studies. Peak urinary flow rates of less than 15 milliliters (mls) per second indicate significant urinary obstruction and flow rates of less than 5 mls/second are felt to be an indication for prompt surgical relief of the obstruction.
Prostate specific antigen (PSA) is a serum protease that is widely used as an indicator of disease severity in both BPH and CaP. Not only are prostatic tissues the only source of PSA but serum PSA levels closely correlate with the total amount of prostate tissue present in the body at any given time. Treatments that reduce the tumor mass in CaP or that induce regression of BPH will demonstrate a reduction in serum levels of PSA.
Current medical treatments of BPH include surgery; systemic therapy with alpha-adrenergic blocking agents such as doxazosin, terazosin, prazosin, alfuzosin, R(+)-terazosin, bunazosin, indoramin and tamulosin; alteration of testosterone metabolism; and therapy with an oral herbal medicine extracted from the saw palmetto (Serenoa repens). Huff (U.S. Pat. No. 5,760,054) discloses a number of more specific alpha 1C adrenergic receptor antagonists that may be utilized in the treatment of BPH.
Treatment of BPH with alpha-adrenergic blocking agents is believed to exert beneficial effects by reducing the adrenergic tone of the smooth muscle cells in the prostate via the alpha-1 receptors. Excessive alpha adrenergic tone in the prostatic smooth muscle cells results in a reversible narrowing of the diameter of the urinary outflow tract as it courses through the prostate. This dynamic component of BPH is believed to be the pathophysiology of BPH in men with small prostates. Oral administration of alpha blockers leading to decreased alpha-1 adrenergic tone is felt to result in relaxation of prostatic smooth muscle with a resultant functional improvement in obstructive urinary tract symptoms such as hesitation, dribbling and nocturia. Alpha-adrenergic blocking agents are therefore best used in men with small prostates where smooth muscle contraction is likely to be the primary contributor to the obstructive symptoms. A meta-analysis of placebo-controlled studies of alpha blockers shows improvement in the peak urinary flow rates by 1.5 ml/sec (LM Eri et al, “Alpha-blockade in the treatment of symptomatic benign prostatic hypertrophy,” J Urol 1995; 154:923-934).
Another approach taken in the medical treatment of BPH involves altering the metabolism of testosterone. Testosterone is converted by 5alpha-reductase into dihydrotestosterone, a compound that stimulates tissue growth in the prostate. This enzyme exists in at least two isoenzyme forms, Type I and Type II. For reasons that are not known, the ratio of dihydrotestosterone to testosterone present in the blood increases with age. The conversion to dihydrotestosterone greatly increases the potency of testosterone in many tissues including the prostate. The growth of the prostate tissue in BPH is exacerbated by the increased ratio of dihydrotestosterone to testosterone that accompanies aging. Finasteride is a drug specifically developed to block the reduction of testosterone to dihydrotestosterone by 5alpha-reductase. Oral administration of finasteride is approved by the FDA as a treatment for the symptoms of BPH. Finasteride has a gradual onset of action resulting in a 70% reduction in se
Killos Paul J.
Rothwell Figg Ernst & Manbeck P.C.
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