Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Conjugate or complex
Reexamination Certificate
2000-01-20
2001-03-13
Tate, Christopher (Department: 1651)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Conjugate or complex
C514S254080
Reexamination Certificate
active
06200573
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a novel and improved method of medical management for men with lower urinary tract symptoms (LUTS) and benign prostatic hyperplasia (BPH), involving combination therapy of administering therapeutically effective amounts of an &agr;
1
-adrenergic antagonist, i.e., terazosin in combination with a phytotherapeutic agent,
Serenoa repens
(saw palmetto) extract.
2. Description of the Prior Art
Benign prostatic hyperplasia (BPH) is a common health related condition that affects many men as they age. Histologic changes that typify BPH are present in 50% of men by age 60 and approximately 90% by age 85 (Berry S J, Coffey D S, Walsh P C, Ewing L L. The development of human benign prostatic hyperplasia with age.
J Urol.
1984; 132:474-479). BPH has a major impact on quality of life and exacts a heavy toll upon healthcare resources, including physicians, hospitals, and surgical facilities. In the United States, treatment of BPH exceeds $2 billion in costs, accounts for 1.7 million physician office visits, (Guess H A. Benign prostatic hyperplasia antecedents and natural history.
Epidemiol Rev.
1992; 14:131-153) and results in more than 300,000 prostatectomies annually (McConnell J D, Barry M J, Bruskewitz R C.
Benign Prostatic Hyperplasia.
Rockville, Md.: Agency for Health Care Policy and Research, Public Health Service, US Dept of Health and Human Services; 1994. Clinical Practice Guideline No. 8, AHCPR publication 94-0582).
Benign prostatic hyperplasia is a heterogeneous disorder shown in studies to be caused by hormonal factors, growth factors, stromal-epithelial interactions, and aging. It is a progressive condition, which results in increased frequency of urination, nocturia, a weak urine stream, hesitancy or delay in starting the urine flow and incomplete bladder emptying. Chronic consequences of BPH can include hypertrophy of bladder smooth muscle, a decompensated bladder, an increased incidence of urinary tract infection, urinary stone formation and renal failure.
Anatomically, the prostate is a fibromuscular and glandular organ that encircles the urethra at the bladder neck. It is situated in the true pelvis below the pubic bone and in front of the rectum. Its upper end (base) is continuous with the neck of the bladder, and its lower end (apex) rests on the pelvic floor. The urethra runs through the prostate from base to apex. The normal prostate is approximately 20 cc in size (volume) and measures between 3 and 4 cm at its widest portion; it is 4-6 cm in length and 2-3 cm in thickness. Structurally it is composed of fibromuscular tissue (30-50%) and glandular epithelial cells (50-70%). The fibromuscular component is present mostly anteriorly, while the glandular element is mostly in the posterior and lateral aspects of the organ. Anteriorly and laterally, a capsule composed of fibrous and smooth muscle tissue surrounds the prostate.
It is widely accepted that obstruction secondary to BPH occurs as a result of two factors: A dynamic component resulting from contraction of smooth muscle of the prostate and prostatic urethra mediated primarily by &agr;-adrenergic receptors; and a mechanical component related to the presence of a mass of hyperplastic acinar or stromal tissue, which compresses and narrows the urethral lumen (Caine M: Alpha-adrenergic blockers for the treatment of benign prostatic hyperplasia.
Urol Clin North Am
1990; 17:641).
The ratio of epithelium to smooth muscle in the prostate can vary substantially among individual men, from 1:3 to 4:1. In general, however, larger prostates contain more androgen-dependent epithelial elements than smaller glands, which contain a higher proportion of smooth muscle. In either case, the outcome of BPH may be urethral obstruction, induced dynamically by smooth muscle contraction and mechanically by epithelial overgrowth, or by a combination of both.
After ruling out alternative causes of voiding disturbances, clinicians rely on surrogate markers to determine the presence of BPH. These include subjective assessments of lower urinary tract symptoms (LUTS) and objective measurements of flow rate and prostate volume. In 1993, the American Urological Association (AUA) developed a questionnaire to quantitate the severity of symptoms in patients with BPH (Barry M F, Fowler F J, O'Leary M P, et al, and the Measurement Committee of the American Urologic Association symptom index for benign prostatic hyperplasia.
J Urol.
1992; 148:1549-1557). The AUA Symptom Index (AUASI) consists of seven questions related to the severity of urinary frequency, nocturia, weak urinary stream hesitancy intermittency, incomplete emptying, and urgency, each of which has a score of (0 to 5) . The maximum score is therefore 35. Patients with scores of (0 to 7) are good candidates for watchful waiting with periodic reevaluation. Men with moderate (8 to 19) to severe (20 to 35) scores usually require therapy to avoid complications.
A number of methodologies can be employed to estimate prostate volume, including magnetic resonance imaging (MRI), transrectal ultrasonography (TRUS), digital rectal examination (DRE), and serum prostate specific antigen (PSA) level. DRE and PSA are by far the most practical and cost effective means of estimating prostate volume. PSA is a glycoprotein that is secreted in the cytoplasm of prostatic cells. Its function is to aid in the liquefaction of semen. Serum PSA is a useful proxy for prostate volume, according to a direct comparison of serum PSA levels and prostate volumes measured using TRUS or MRI. A strong log-log linear relationship was found between the two, although the slope of the relationship changes with advancing age. In light of these results, serum PSA may be used as a surrogate for prostate volume to identify patients with prostate enlargement over certain threshold sizes.
Epidemiological studies show that men with prostate volumes greater than 30 cc have a three fold higher risk of acute urinary retention (Jacobsen S J, Jacobson D J, Girman C J, Roberts R O, Rhodes T. Guess H A, Lieber M M. Natural History of Prostatism: Risk Factors for Acute Urinary Retention,
J Urol.
1997; 158:481-487). Similarly, a recent clinical trial demonstrated that men with serum PSA levels greater than 1.4 ng/ml and 3.3 ng/ml were 2.0 and 4.2 times more likely to develop acute urinary retention respectively, than men with Serum PSA levels less than 1.4 ng/ml (McConnell J D, Bruskewitz R, Walsh P, et al for the PROSCAR Long-Term Efficacy and Safety Study (PLESS) Group. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia.
N Engl J Med.
1998; 338(9): 557-563).
Estimations of prostate volume, either by DRE or serum PSA level, may be used to appropriately guide the selection of therapeutic alternatives, particularly when a goal of therapy is reduction of the risk for disease progression, development of urinary retention, and the need for BPH related surgery.
Treatment options for BPH include lifestyle modification, device, surgery, pharmacologic, and phytotherapeutic interventions. There are two classes of pharmacologic intervention: &agr;-antagonists, which act via adrenergic pathways, and 5&agr;-reductase inhibitors, which act via hormonal mechanisms. Alpha-Antagonists can be effective in relieving symptoms of BPH, whereas the 5&agr;-reductase inhibitors have been shown to reduce prostate volume.
Serenoa repens
(saw palmetto) extract, a popular phytotherapeutic agent, has been shown to reduce prostate volume and to a lesser extent relieve symptoms and improve urine flow.
The therapeutic rationale for &agr;-adrenergic blockade is two fold. A very large percentage of the hyperplastic prostate gland, at least 40% is comprised of smooth muscle, and that smooth muscle has a very high density of &agr;-adrenergic receptors (Lepor H. &agr;
1
-adrenoceptor selectivity: clinical or theoretical benefit?
Br J Urol.
1995; 76 9 suppl. 1): 57-61). The sympatheti
Gunter, Jr. Charles D.
Meller Michael V.
StarCor Pharmaceuticals, Inc.
Tate Christopher
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