WO2007141661A2

WO2007141661A2 - Herbal compositions for the prevention or treatment of benign prostatic hyperplasia

Info

Publication number: WO2007141661A2
Application number: PCT/IB2007/002331
Authority: WO
Inventors: Tracey Anne Seipel
Original assignee: Tracey Anne Seipel
Priority date: 2006-02-22
Filing date: 2007-02-21
Publication date: 2007-12-13
Also published as: TW200800242A; WO2007141661A3

Abstract

The present invention relates to herbal compositions for the prevention or treatment of disorders of the prostate, for example, benign prostatic hyperplasia (BPH), prostatitis, and prostatic intraepithelial neoplasia. Specifically, the invention provides compounds that contain C. nυrvala and E. arvense and methods of use thereof.

Description

HERBAL COMPOSITIONS FOR THE PREVENTION OR TREATMENT OF BENIGN PROSTATIC HYPERPLASIA

FIELD OF THE INVENTION

The present invention relates to herbal compositions for the prevention or treatment of disorders of the prostate, for example, enlarged prostate or benign prostatic hyperplasia (hereinafter, "BPH"), prostatitis, or prostatic intraepithelial neoplasia.

BACKGROUND OF THE INVENTION

The prostate is a gland present only in men and is located just below the bladder and surrounds the urethra. Benign prostatic hyperplasia (BPH) - the condition known as enlarged prostate - is caused by an overgrowth of prostate cells. When the prostate enlarges, it constricts the urethra and reduces the flow of urine, making it increasingly difficult to empty the bladder. BPH is a common condition of aging. According to the National Institutes of Health (NIH)₁ BPH affects more than 50% of men over age 60 and as many as 90% of men over the age of 70. The cause of BPH is unknown. It is possible that the condition is associated with hormonal changes that occur as men age. The testes produce the hormone testosterone, which is converted to dihydrotestosterone (DHT) and estradiol (estrogen) in certain tissues. High levels of DHT may accumulate and cause hyperplasia. However, the reason for the DHT increase remains a subject of research.

Prostatitis is a term used to describe inflammatory conditions of the prostate gland. It is thought that most cases of prostatitis result from bacterial infection, but evidence of infection is not always found. Prostatitis can affect men of any age and it is estimated that 50% of men experience the disorder during their lifetime. Prostatitis is the most common urological disorder in men over the age of 50 and the third most common disorder in men younger than 50. There are four types of prostatitis: acute bacterial prostatitis (ABP) is inflammation of the prostate gland caused by bacteria such as Escherichia coli and Klebsiella; chronic bacterial prostatitis (CBP) is a recurrent infection and inflammation of the prostate and urinary tract; nonbacterial prostatitis is an inflamed prostate without bacterial infection; and prostatodynia, sometimes called chronic pelvic pain syndrome (CPPS), is the occurrence of prostatitis symptoms, without inflammation or bacterial infection. Prostatic intraepithelial neoplasia (PIN) has been identified as a precursor lesion to prostatic carcinoma. PIN refers to the precancerous end of a morphologic spectrum involving cellular proliferation within prostatic ducts, ductules, and acini. Bostwick and Brawer introduced the term PIN in 1987. At an international conference in 1989, the term PIN replaced a variety of terms (e.g., intraductal hyperplasia, hyperplasia with malignant change, large acinar atypical hyperplasia, marked atypia, ductal-acinar dysplasia.) The frequency of PIN in men with prostate cancer is significantly higher than in those without cancer. PIN appears to precede cancer by more than 10 years, with a parallel age-related increase in the frequency of PIN and cancer. PIN has been found in 9% of men in the second decade of life, 22% of men in the third decade, and 40% of men in the fourth decade. By the time men reach age 80 years, the prevalence of PIN is 70%.

Symptom of the above prostate disorders are similar. Common symptoms are urinary and include dribbling after voiding; feeling that the bladder has not emptied completely after urination; frequent urination, particularly at night (i.e., nocturia); hesitant, interrupted, or weak urine stream caused by decreased force; leakage of urine (i.e., overflow incontinence); pushing or straining to begin urination; recurrent, sudden, urgent need to urinate; and blood in the urine (i.e., hematuria) caused by straining to void.

There are two main classes of drugs that are prescribed for treating prostate disorders: alpha-blockers and 5-alpha-reductase inhibitors.

Alpha-blockers relax the smooth muscles of the arteries, the prostate, and the bladder neck. Relaxing the smooth muscles around the bladder neck helps relieve urinary obstruction. While alpha-blockers help alleviate some of the symptoms, this drug does not cure BPH. There are several different alpha-blockers. Currently, these are alfuzosin (Xatral), doxazosin (Cardura), indoramin (Doralese), prazosin (Hypovase), terazosin (Hytrin BPH), and tamsulosin (Flomax MR). Side effects can include headaches, dizziness, low blood pressure, fatigue, weakness, and difficulty breathing. Long-term risks and benefits have not been studied.

5-alpha-reductase inhibitors inhibit the production of the enzyme that converts testosterone to DHT. Thus, 5-alpha-reductase inhibitors are able to reverse BPH to some extent and shrink the prostate. Side effects include reduced libido, impotence, problems with ejaculation, breast tenderness and enlargement, and reduced sperm count. Long-term risks and benefits have not been studied. Safety of 5 alpha reductase inhibitors is a concern for pregnant women who may be exposed to broken capsules, and patients on this medication should stop for 6 months before donating blood.

Surgery is also an option for relief of symptoms of BPH and prostatitis and is recommended for patients who experience serious complications, and has the most complications including urinary incontinence, overactive bladder and a possible worsening of urinary symptoms as well as impotence, retrograde ejaculation (dry climax), and possibly sterility. Prostatectomy complications include incontinence and impotence.

Natural therapies may be used to treat prostate disorders. Saw palmetto (Serenoa repens) acts as a 5-alpha-reductase inhibitor reducing the production of DHT and also preventing DHT from binding to the prostate. Schneider et al. , Fortschr. Med. 113: 37-40 ( 1995); Kock and Biber, Urologe 334: 90-95 (1994). Side effects include mild digestive distress as well as some of the side effects associated with the 5-alpha-reductase inhibiting drug medications, such as mild pruritis, headache, hypertension, erectile dysfunction, ejaculatory disorders, and decreased libido. Pygeum (Pygeum africanυm) contains three compounds that may help the prostate: pentacyclic triterpenoids, which have a diuretic action; phytosterols, which have anti-inflammatory activity; and ferulic esters, which help rid the prostate of any cholesterol deposits that accompany BPH. Andro and Riffaud, Curr. Ther. Res. 56: 796-817 (1995). Stinging nettles (Urtica dioica) can also reduce BPH symptoms and may increase urinary volume and the maximum flow rate of urine in men with early-stage BPH. Kock and Biber, Urologe 334:90-95 (1994). Side effects include digestive distress.

All of the mentioned treatment options for prostate disorders have some associated side effects. Pharmaceutical drug and herbal treatment options commonly do not completely resolve symptoms of urinary incontinence and overactive bladder that may be associated with the disorders. There is currently a need for new compositions for the prevention and treatment of prostate disorders and its associated symptoms, including overactive bladder (OAB) and urinary incontinence (Ul), without the unwanted side effects.

BRIEF SUMMARY OF THE INVENTION

The present invention provides methods of preventing or treating prostate disorders. In one embodiment, the prostate disorder can be, for example, an enlarged prostate or benign prostatic hyperplasia (hereinafter, "BPH"), prostatitis, or prostatic intraepithelial neoplasia.

In one embodiment, the invention provides a method of administering to a subject at risk of a prostate disorder a herb-containing composition comprising: a Crateva nurvala (C. nurvala) stem/bark preparation present at a concentration at least about 1,000 mg dry weight equivalents per oral dosage unit; an Equisetum arvense (E. arvense) herb preparation at a concentration of at least about 670 mg dry weight equivalents per oral dosage unit; a silicon concentration of at least about 32.5 mg dry weight equivalents per oral dosage unit; a phosphorous concentration of at least about 24.9 mg dry weight equivalents per oral dosage unit; a magnesium concentration of at least about 14.5 mg dry weight equivalents per oral dosage unit; and a calcium concentration of at least about 16.3 mg dry weight equivalents per oral dosage unit. Herb-containing compositions of the invention can be formulated in a dry delivery system, liquid delivery system, or a controlled- release vehicle. The herb-containing compositions of the invention are formulated as oral dosage units which include a tablet; dry powder; capsule; and caplet.

The C. nurvala stem/bark preparation is present at a concentration at least about 1,000 mg dry weight equivalents per oral dosage unit. That is, the starting material is 1,000 mg of C. nυrvala dry stem/bark. This starting material is eventually concentrated during the manufacture process to a ratio of 10:1 which equates to 100 mg of C. nυrvala preparation. Accordingly, 100 mg of C. nυrvala stem/bark preparation (which is concentrated) is equivalent to 1,000 mg dry weight of C. nυrvala stem/bark or 1,000 mg of C. nυrvala dry stem/bark starting material.

The E. arvense herb preparation is present at a concentration of at least about 670 mg dry weight equivalents per oral dosage unit. That is, the starting material is 670 mg of E. arvense herb. This starting material is eventually concentrated during the manufacture process to a ratio of 4:1 or 5:1 which equates to 167 mg or 134 mg of E. arvense herb preparation. So. for example, 167 mg of E. arvense herb preparation (which is concentrated) is equivalent to 670 mg dry weight of E. arvense herb or 670 mg of E. arvense dry herb starting material. In one embodiment, the standardized E. arvense herb preparation is derived from the stem parts of the E. arvense herb, i.e., a standardized E. arvense stem extract preparation.

In certain aspects of the present invention, it has been determined that batch variation in the silicon content and/or flavonoid content expressed as isoquercetrin of E. arvense herb preparations can have negative effects on the biological activity of the composition of the present invention. This problem has been resolved by the present invention by providing E. arvense herb preparations with optimized, standardized silicon content and/or flavonoid content expressed as isoquercetrin. In one embodiment, the invention provides a herb-containing composition, comprising a C. nυrvala stem/bark preparation and a standardized E. arvense herb preparation with a silicon content from about 3% to about 13% silicon based on total dry weight of the E. arvense preparation, wherein the herb-containing composition is formulated as an oral dosage unit. Accordingly, for 1 ,500 mg dry weight of E. arvense herb or 1 ,500 mg of E. arvense dry herb starting material, which produces 300 mg of E. arvense herb preparation (which is concentrated), a silicon content from about 3% to about 13% would represent approximately 9 to 39 mg silicon.

In one embodiment, the C. nυrvala stem/bark preparation is present in the herb-containing composition at a concentration from about 100 mg to about 4,000 mg dry weight equivalents per oral dosage unit. In one embodiment, the C. nυrvala stem/bark preparation is present in the herb- containing composition at a concentration from about 500 mg to about 2,000 mg dry weight equivalents per oral dosage unit. In one embodiment, the C. nυrvala stem/bark preparation is present in the herb-containing composition at a concentration from about 800 mg to about 1 ,200 mg dry weight equivalents per oral dosage unit. In one embodiment, the standardized E. arvense preparation is present in the herb-containing composition at a concentration from about 1 mg to about 3,000 mg dry weight equivalents per oral dosage unit. In one embodiment, the standardized E. arvense preparation is present in the herb-containing composition at a concentration from about 100 mg to about 2,000 mg dry weight equivalents per oral dosage unit. In one embodiment, the standardized E. arvense preparation is present in the herb-containing composition at a concentration from about 500 mg to about 1,000 mg dry weight equivalents per oral dosage unit. In one embodiment, the standardized E. arvense preparation is present in the herb-containing composition at a concentration from about 600 mg to about 850 mg dry weight equivalents per oral dosage unit.

In another embodiment, the herb-containing composition further comprises anhydrous colloidal silica, wherein the total silicon content of the herb-containing composition is from about 3 mg dry weight equivalents to about 71 mg dry weight equivalents per oral dosage unit. In one embodiment, the herb-containing composition further comprises anhydrous colloidal silica, wherein the total silicon content of the herb-containing composition is from about 5 mg dry weight equivalents to about 45 mg dry weight equivalents per oral dosage unit. In one embodiment, the herb-containing composition further comprises anhydrous colloidal silica, wherein the total silicon content of the herb-containing composition is from about 9 mg dry weight equivalents to about 34 mg dry weight equivalents per oral dosage unit. In one embodiment, the standardized E. arvense herb preparation further comprises a total flavonoid content from about 0.01% to about 3% total flavonoids based on the total dry weight of the E. arvense preparation, wherein the total flavonoid content is expressed as isoquercetrin. In one embodiment, the standardized E. arvense herb preparation further comprises a total flavonoid content from about 0.1% to about 2.5% total flavonoids based on the total dry weight of the E. arvense preparation and expressed as isoquercetrin. In one embodiment, the standardized E. arvense herb preparation further comprises a total flavonoid content from about 0.5% to about 1.5% total flavonoids based on the total dry weight of the E. arvense preparation, wherein the total flavonoid content is expressed as isoquercetrin. In one embodiment, the standardized E. arvense herb preparation further comprises a total flavonoid content from at least about 0.8% total flavonoids based on the total dry weight of the E. arvense preparation, wherein the total flavonoid content is expressed as isoquercetrin.

In one embodiment, the herb-containing composition further comprises phosphorous, wherein the phosphorous is present at a concentration from about 5 mg dry weight equivalents to about 60 mg dry weight equivalents per oral dosage unit. In one embodiment, the herb- containing composition further comprises phosphorous, wherein the phosphorous is present at a concentration from about 10 mg dry weight equivalents to about 50 mg dry weight equivalents per oral dosage unit. In one embodiment, the herb-containing composition, further comprises phosphorous, wherein the phosphorous is present at a concentration from about 20 mg dry weight equivalents to about 30 mg dry weight equivalents per oral dosage unit. In one embodiment, the herb-containing composition further comprises calcium, wherein the calcium is present at a concentration from about 1 mg dry weight equivalents to about 30 mg dry weight equivalents per oral dosage unit. In one embodiment, the herb-containing composition of claim 1 , further comprises calcium, wherein the calcium is present at a concentration from about 5 mg dry weight equivalents to about 25 mg dry weight equivalents per oral dosage unit. In one embodiment, the herb-containing composition, further comprises calcium, wherein the calcium is present at a concentration from about 10 mg dry weight equivalents to about 20 mg dry weight equivalents per oral dosage unit.

In one embodiment, the herb-containing composition of further comprising magnesium, wherein the magnesium is present at a concentration from about 1 mg dry weight equivalents to about 30 mg dry weight equivalents per oral dosage unit. In one embodiment, the herb-containing composition, further comprising magnesium, wherein the magnesium is present at a concentration from about 5 mg dry weight equivalents to about 25 mg dry weight equivalents per oral dosage unit. In one embodiment, the herb-containing composition, further comprising magnesium, wherein the magnesium is present at a concentration from about 10 mg dry weight equivalents to about 20 mg dry weight equivalents per oral dosage unit. In one embodiment, the herb-containing composition further comprises or is coadministered with at least one of: (a) a Serenoa repens/serrυlata (Saw palmetto) berry preparation, wherein Serenoa repens/serrυlata is present at a concentration of at least about 107 mg of extract standardized to contain approx 85% fatty acids and sterols per oral dosage unit; (b) a Pygeum africanum bark preparation, wherein Pygeum africanυm is present at a concentration of at least about 100 mg dry weight, standardized to contain 2.5 mg phytosterols per oral dosage unit; (c) an Urtica dioica (stinging nettles) root preparation, wherein Urtica dioica is present at a concentration of at least about 100 mg extract per oral dosage unit; (d) Lycopersicon esculentum (tomato) fruit, wherein Lycopersicon esculentum is present at a concentration of at least about 333 mg, standardized to contain 0.1 mg of Lycopene, per oral dosage unit; (e) a Curcubita pepo (pumpkin seed) seed preparation, wherein Curcubita pepo is present at a concentration of at least about 10 g dry weight per oral dosage unit; (f) zinc, wherein the zinc is present at a concentration of at least about 1 mg dry weight equivalents per oral dosage unit; (g) copper, wherein copper is present at a concentration of at least about 1 mg dry weight equivalents per oral dosage unit; (h) selenium, wherein selenium is present at a concentration of at least about 5 μg dry weight equivalents per oral dosage unit; (i) cholecalciferol (Vitamin D3), wherein cholecalciferol is present at a concentration of at least about 200 IU dry weight equivalents per oral dosage unit; (j) vitamin E, wherein vitamin E is present at a concentration of at least about 50 IU dry weight equivalents per oral dosage unit; (k) vitamin B6, wherein vitamin B6 is present at a concentration of at least about 25 mg dry weight equivalents per oral dosage unit; (I) vitamin C, wherein vitamin C is present at a concentration of at least about 100 mg dry weight equivalents per oral dosage unit; (m) glutamic acid (as l-glutamic acid), wherein glutamic acid is present at a concentration of at least about 200 mg dry weight equivalents per oral dosage unit; (n) glycine, wherein glycine is present at a concentration of at least about 200 mg dry weight equivalents per oral dosage unit; and (o) alanine, wherein alanine is present at a concentration of at least about 200 mg dry weight equivalents per oral dosage unit. In one embodiment, the invention provides a herb-containing composition, comprising: a

C. nυrvala stem/bark preparation present at a concentration at least about 1 ,000 mg dry weight equivalents per oral dosage unit; an E. arvense stem extract preparation present at a concentration of at least about 670 mg dry weight equivalents per oral dosage unit; a total Saw palmetto (Serenoa repens/serrυlata) concentration of at least about 1 ,070 mg; a total concentration of at least about 2.92 g Tomato {Lycopersicon esculentum), standardized to contain at least about 500 μg Lycopene; a total concentration of at least about 5 mg zinc; a total concentration of at least about 8 μg dry weight equivalents selenium.

In one embodiment, the invention provides a pharmaceutical composition comprising the herb-containing composition of the invention and a pharmaceutically-acceptable carrier. In another aspect, the invention provides methods of preventing or treating a prostate disorder in a subject, by administering to the subject a herb-containing composition of the invention in an amount sufficient to prevent or treat the prostate disorder.

In another aspect, the invention provides a method of preventing or treating a disorder of the prostate, the method comprising administering to a subject afflicted with or at risk of the disorder of the prostate a herb-containing composition comprising: at least about 1,000 mg of Crateva nurvala stem/bark preparation and at least about 670 mg of a standardized Equisetum arvense stem extract, wherein the administration of the composition reduces the symptoms of the disorder of the prostate. In one embodiment of the method, the herb-containing composition is formulated in a dry delivery system. In one embodiment of the method, the herb-containing composition is formulated in a liquid delivery system. In one embodiment of the method, the herb- containing composition is formulated in a controlled-release vehicle. In one embodiment of the method, the oral dosage unit is selected from the group consisting of: a tablet; dry powder; capsule; and caplet. In some embodiments of the method, the herb-containing composition further comprises at least one compound selected from the group consisting of: (a) a Serenoa repens/serrulata (Saw palmetto) berry preparation present at a concentration of at least about 107 mg of extract standardized to contain approx 85% fatty acids and sterols per oral dosage unit; (b) a Pygeυm africanum bark preparation present at a concentration of at least about 100 mg dry weight, standardized to contain 2.5 mg phytosterols per oral dosage unit; (c) an Urtica dioica (stinging nettles) root preparation present at a concentration of at least about 100 mg extract per oral dosage unit; (d) a Lycopersicon esculentum (tomato) fruit concentration of at least about 333 mg, standardized to contain 0.1 mg of Lycopene, per oral dosage unit; (e) a Curcubita pepo (pumpkin seed) seed preparation present at a concentration of at least about 10 g dry weight per oral dosage unit; (f) a zinc concentration of at least about 3 mg dry weight equivalents per oral dosage unit; (g) a copper concentration of at least about 1 mg dry weight equivalents per oral dosage unit; (h) selenium concentration of at least about 5 μg dry weight equivalents per oral dosage unit; (i) a cholecalciferol (Vitamin D3) concentration of at least about 200 IU dry weight equivalents per oral dosage unit; (j) a vitamin E concentration of at least about 50 IU dry weight equivalents per oral dosage unit; (k) a vitamin B6 concentration of at least about 25 mg dry weight equivalents per oral dosage unit; (I) a vitamin C concentration of at least about 100 mg dry weight equivalents per oral dosage unit; (m) a glutamic acid (as l-glutamic acid) concentration of at least about 200 mg dry weight equivalents per oral dosage unit; (n) a glycine concentration of at least about 200 mg dry weight equivalents per oral dosage unit; and (o) an alanine concentration of at least about 200 mg dry weight equivalents per oral dosage unit. In some embodiments of the methods, the composition is co-administered with a second composition comprising at least one compound selected from the group consisting of: (a) a Serenoa repens/serrulata (Saw palmetto) berry preparation present at a concentration of at least about 107 mg of extract standardized to contain approx 85% fatty acids and sterols per oral dosage unit; (b) a Pygeum africanum bark preparation present at a concentration of at least about 100 mg dry weight, standardized to contain 2.5 mg phytosterols per oral dosage unit; (c) an Urtica dioica (stinging nettles) root preparation present at a concentration of at least about 100 mg extract per oral dosage unit; (d) a Lycopersicon esculentum (tomato) fruit concentration of at least about 333 mg, standardized to contain 0.1 mg of Lycopene, per oral dosage unit; (e) a Curcubita pepo (pumpkin seed) seed preparation present at a concentration of at least about 10 g dry weight per oral dosage unit; (f) a zinc concentration of at least about 3 mg dry weight equivalents per oral dosage unit; (g) a copper concentration of at least about 1 mg dry weight equivalents per oral dosage unit; (h) a selenium concentration of at least about 5 μg dry weight equivalents per oral dosage unit; (i) a cholecalciferol (Vitamin D3) concentration of at least about 200 IU dry weight equivalents per oral dosage unit; 0) a vitamin E concentration of at least about 50 IU dry weight equivalents per oral dosage unit; (k) a vitamin B6 concentration of at least about 25 mg dry weight equivalents per oral dosage unit; (I) a vitamin C concentration of at least about 100 mg dry weight equivalents per oral dosage unit; (m) a glutamic acid (as l-glutamic acid) concentration of at least about 200 mg dry weight equivalents per oral dosage unit; (n) a glycine concentration of at least about 200 mg dry weight equivalents per oral dosage unit; and (o) an alanine concentration of at least about 200 mg dry weight equivalents per oral dosage unit. In one embodiment of the method, the composition is administered to the subject contemporaneously with the second composition. In one embodiment of the method, the composition is administered to the subject before the second composition is administered to the subject. In one embodiment of the method, the composition is administered to the subject after the second composition is administered to the subject.

In another aspect, the invention provides, a herb-containing composition, comprising: (a) a Crateva nυrvata stem/bark preparation present at a concentration of at least about 1 ,000 mg dry weight equivalents per oral dosage unit; (b) a standardized Equisetυm arvense stem extract preparation present at a concentration of at least about 1 ,500 mg dry weight equivalents per oral dosage unit; and (c) at least one compound selected from the group consisting of: (i) a Serenoa repens/serrulata (Saw palmetto) berry preparation present at a concentration of at least about 107 mg of extract standardized to contain approx 85% fatty acids and sterols per oral dosage unit; (ii) a Pygeum africanum bark preparation present at a concentration of at least about 100 mg dry weight, standardized to contain 2.5 mg phytosterols per oral dosage unit; (iii) an Urt/ca dioica (stinging nettles) root preparation present at a concentration of at least about 100 mg extract per oral dosage unit; (iv) a Lycopersicon esculentum (tomato) fruit concentration of at least about 333 mg, standardized to contain 0.1 mg of Lycopene, per oral dosage unit; (v) a Curcubita pepo (pumpkin seed) seed preparation present at a concentration of at least about 10 g dry weight per oral dosage unit; (vi) a zinc concentration of at least about 1 mg dry weight equivalents per oral dosage unit; (vii) a copper concentration of at least about 1 mg dry weight equivalents per oral dosage unit; (viii) a selenium concentration of at least about 5 μg dry weight equivalents per oral dosage unit; (ix) a cholecalciferol (Vitamin D3) concentration of at least about 200 IU dry weight equivalents per oral dosage unit; (x) a vitamin E concentration of at least about 50 IU dry weight equivalents per oral dosage unit; (xi) a vitamin B6 concentration of at least about 25 mg dry weight equivalents per oral dosage unit; (xii) a vitamin C concentration of at least about 100 mg dry weight equivalents per oral dosage unit; (xiii) a glutamic acid (as l-glutamic acid) concentration of at least about 200 mg dry weight equivalents per oral dosage unit; (xiv) a glycine concentration of at least about 200 mg dry weight equivalents per oral dosage unit; and (xv) an alanine concentration of at least about 200 mg dry weight equivalents per oral dosage unit. In another embodiment, the invention provides, a herb-containing composition, comprising: (a) a Crateva nurvala stem/bark preparation present at a concentration of 1 ,000mg dry weight equivalents per oral dosage unit; (b) a standardized Eqυisetυm arvense stem extract preparation present at a concentration of 670 mg dry weight equivalents per oral dosage unit; (c) a Serenoa repens/serrulata (Saw palmetto) berry preparation present at a concentration of 107 mg of extract per oral dosage unit; (d) a Lycopersicon esculentum (tomato) fruit concentration of 2.92 g, standardized to contain 0.5 mg of Lycopene, per oral dosage unit; (e) a zinc concentration of 5 mg dry weight equivalents per oral dosage unit; and (f) a selenium concentration of 8 μg dry weight equivalents per oral dosage unit.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will be more fully understood by reference to the following drawings which are for illustrative purposes only:

FIG. 1 is a histogram graph showing the percentage of "extremely bothered" responses during clinical assessment of a herb-based cream to treat urinary incontinence.

FIG. 2 is a histogram graph showing the percentage of "extremely bothered" responses during clinical assessment of a herb-based tablet to treat urinary incontinence.

FIG. 3 is a histogram graph showing the percentage of "extremely bothered" responses during clinical assessment of a herb-based tablet to treat urinary incontinence. FIG. 4— FIG. 11 are histogram graphs showing the percentage of "bothered" responses during clinical assessments of a herb-based tablet to treat urinary incontinence and overactive bladder.

FIG. 12 is a histogram graph showing the percent reduction of people experiencing the symptoms of urinary incontinence and overactive bladder after three months of various herb- based tablet treatments.

DETAILED DESCRIPTION OF THE INVENTION

It is to be appreciated therefore that certain aspects, modes, embodiments, variations and features of the invention described below in various levels of detail in order to provide a substantial understanding of the present invention. In general, such disclosure provides beneficial herb-containing compositions, combinations of such compositions with other dietary supplement compositions, and related methods of producing and using same. Accordingly, the various aspects of the present invention relate to therapeutic or prophylactic uses of certain particular herb-based compositions in order to prevent or treat a disease, injury or condition related to enlarged prostate. Accordingly, various particular embodiments that illustrate these aspects follow. It is to be appreciated that the various modes of treatment or prevention of medical conditions as described are intended to mean "substantial", which includes total but also less than total treatment or prevention, and wherein some biologically or medically relevant result is achieved.

DEFINITIONS A "subject," as used herein, is preferably a mammal, such as a human, but can also be an animal, e.g., domestic animals (e.g., dogs, cats and the like), farm animals {e.g., cows, sheep, pigs, horses and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like).

An "effective amount" of a composition, as used herein, is a quantity sufficient to achieve a desired therapeutic and/or prophylactic effect, for example, an amount which results in the prevention of or a decrease in the symptoms associated with a disease that is being treated. The amount of composition administered to the subject will depend on the type and severity of the disease and on the characteristics of the individual, such as general health, age, sex, body weight and tolerance to drugs. It will also depend on the degree, severity and type of disease. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. Typically, an effective amount of the compositions of the present invention, sufficient for achieving a therapeutic or prophylactic effect.

It is advantageous to formulate oral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active composition calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the dietary supplement and the particular therapeutic effect to be achieved, and the limitations inherent in the art of producing such an active composition for the treatment of individuals. The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration. Oral doses can be taken two-times to four-times daily, until symptom relief is apparent. In one embodiment, oral doses are taken three-times daily, until symptom relief is apparent. Typically, an oral dose is taken three times daily, until symptom relief is apparent. The compositions of the present invention can also be administered in combination with each other, or with one or more additional therapeutic compositions. Crateva nurvala is a moderate-sized tree attaining a height of over 15 meters; it is named after cratevas (Krateuas), a Greek naturalist and physician of the 1st Century B.C. Common throughout India, the much-branched tree with a head of glossy trifoliate leaves looks very majestic when in full bloom from March to May (earlier in the South). The bark of the tree is reported to be used as a demulcent, antipyretic, sedative, alterative and tonic.

Equisetum arvense (botanical synonyms and common names include, e.g., Horsetail; Shave-grass; Bottle-brush; Paddock-pipes; Dutch Rushes; Pewterwort; Shavegrass; pewterwort; bottlebrush; horsetail rush; paddock-pipes; Dutch rushes; mare's tail) is a European herb which grows in moist waste places throughout temperate regions of the world and is cultivated in Yugoslavia. This perennial plant is common to moist loamy or sandy soil all over North America and Eurasia. No other herb in the entire plant kingdom is so rich in silicon as is horsetail. Equisetum is used medicinally. The sterile stems are harvested in summer and dried. The barren stems are useful as medicine, appearing after the fruiting stems have died down, and are used in their entirety, cut off just above the root. The herb is used either fresh or dried, but is said to be most efficacious when fresh. A fluid extract is prepared from it. The ashes of the plant are also employed.

The references cited throughout this application are incorporated herein by reference in their entireties.

HERB-CONTAINING COMPOSITIONS OF THE INVENTION The present invention provides herb-containing compositions useful in a method of prophylaxis or treatment of disorders of the prostate, for example, enlarged prostate or benign prostatic hyperplasia (hereinafter, "BPH"), prostatitis, or prostatic intraepithelial neoplasia. Specifically, the invention identifies compositions that contain C. nurvala and E. arvense that are useful in the prevention and treatment of disorders of the prostate. In one embodiment of the invention, the herb-containing composition contains C. nurvala stem/bark extract and E. arvense herb.

In one embodiment of the invention, the herb-containing composition of the invention is an oral supplement included in a dry delivery system, e.g., tablet, dry powder, and dry meal replacement mixture. In another embodiment, the herb-containing composition of the invention is an oral supplement included in a liquid delivery system, e.g., capsule, caplet, or beverage. In another embodiment, the herb-containing composition of the invention is an oral supplement included in a controlled-release vehicle, e.g., tablet, caplet, and capsule.

In another embodiment, the herb-containing composition of the invention contains from about 100 mg to about 6,000 mg dry weight equivalents C. nurvala bark extract per oral dosage unit. In another embodiment, the herb-containing composition of the invention contains from about 500 mg to about 4,000 mg dry weight equivalents C. nurvala bark extract per oral dosage unit. In another embodiment, the herb-containing composition of the invention contains from about 800 mg to about 1,200 mg dry weight equivalents C. nurvala bark extract per oral dosage unit. To prepare the herb-containing composition of the invention, the bark and stems of

C. nurvala were isolated from the rest the C. nurvala plant and dried. The dried bark and stems of C. nurvala were extracted using 70% (v/v) ethanol/water. The liquid extract was then concentrated to a ratio of 10:1. Maltodextrin was used as an excipient. The final product, i.e., C. nurvala stem/bark extract, used in the herb-containing composition of the invention was a brown to dark brown powder.

In another embodiment of the invention, the E. arvense herb preparation component of the herb-containing composition of the invention is derived from the leaf of the E. arvense herb. In one embodiment of the invention, the E. arvense herb preparation component of the herb- containing composition of the invention is derived from the stem of the E. arvense herb. In another embodiment of the invention, the E. arvense herb preparation component of the herb- containing composition of the invention is derived from a mixture of plant parts of the E. arvense herb. In another embodiment of the invention, the E. arvense herb preparation component of the herb-containing composition of the invention is derived from all the parts of the plant that extend above-ground. In one embodiment, the herb-containing composition of the invention contains from about 1 mg to about 3,000 mg dry weight equivalents E. arvense herb preparation per oral dosage unit. In another embodiment, the herb-containing composition of the invention contains from about 100 mg to about 1,500 mg dry weight equivalents E. arvense herb preparation per oral dosage unit. In another embodiment, the herb-containing composition of the invention contains from about 600 mg to about 800 mg dry weight equivalents E. arvense herb preparation per oral dosage unit. In another embodiment, the herb-containing composition of the invention contains from about 650 mg to about 700 mg dry weight equivalents E. arvense herb preparation per oral dosage unit.

Silicon has been identified as a contributor to the biological activity of E. arvense herb. Non-standardized preparations of E. arvense herb generally contain silicon from about 1.2% to about 6.9% silicon based on total dry weight of preparation. In one aspect of the present invention, it has been determined that batch variation in the silicon content of E. arvense herb preparations can have negative effects on the biological activity of the composition of the present invention. This problem has been resolved by the present invention by providing an E. arvense herb preparation with optimized, standardized silicon content. Accordingly, in one embodiment of the invention, the silicon content of the E. arvense herb preparation in the herb-containing preparation of the invention is standardized. The use of a standardized preparation E. arvense herb is advantageous because the inter-batch variation of silicon is reduced, thus the composition of the present invention yields more consistent preventative or therapeutic effect. In one embodiment, the E. arvense herb preparation is standardized to contain from about 3% silicon to about 13% silicon based on the total dry weight of the E. arvense herb preparation. In another embodiment, the E. arvense herb preparation is standardized to contain from about 5% silicon to about 10% silicon based on the total dry weight of the E. arvense herb preparation. In another embodiment, the E. arvense herb preparation is standardized to contain at least about 6% silicon based on the total dry weight of the E. arvense herb preparation.

In addition to silicon, E. arvense contains about 5 percent of a saponin, designated equisetonin, and several flavone glycosides (a./c.a., flavonoids) including isoquercetrin, galuteolin, and equisetrin. Isoquercetrin (a.k.a, isoquercitrin; Quercetin 3-O-β-D-glucopyranoside; 4H-1- Benzopyran-4-one, 2-(3,4-dihydroxy-phenyl)-3-(β-D-glucofuranosyloxy)-5,7-dihydroxy-). Flavonoids, e.g., isoquercetrin, may have important pharmacological properties. Many flavonoids are diuretic, some are antispasmodic, anti-inflammatory, antiseptic and even anti-tumor. However, the predominant action of the flavonoids as a group is on the vascular system. The flavone glycosides and the saponin likely combine to account for the diuretic action of E. arvense.

In another aspect of the present invention, it has been determined that batch variation in the total flavonoid content (expressed as isoquercetrin content) of E. arvense herb preparations can have negative effects on the biological activity of the composition of the present invention. This problem has been resolved by the present invention by providing an E. arvense herb preparation with optimized, standardized total flavonoid content (expressed as isoquercetrin content). Accordingly, in one embodiment of the invention, the total flavonoid content (expressed as isoquercetrin content) of the E. arvense herb preparation in the herb-containing preparation of the invention is standardized. The use of a standardized preparation E. arvense herb is advantageous because the inter-batch variation of total flavonoid content (expressed as isoquercetrin content) is reduced, thus the composition of the present invention yields more consistent preventative or therapeutic effect. In one embodiment, the E. arvense herb preparation is standardized to contain from about 0.01% flavonoids to about 3% flavonoids based on the total dry weight of the E. arvense herb preparation, wherein the total flavonoids are expressed as isoquercetrin equivalents. In another embodiment, the E. arvense herb preparation is standardized to contain from about 0.1% flavonoids to about 2.5% flavonoids based on the total dry weight of the E. arvense herb preparation, wherein the total flavonoids are expressed as isoquercetrin equivalents. In another embodiment, the E. arvense herb preparation is standardized to contain from about 0.5% flavonoids to about 1.5% flavonoids based on the total dry weight of the E. arvense herb preparation, wherein the total flavonoids are expressed as isoquercetrin equivalents. In another embodiment, the E. arvense herb preparation is standardized to contain at least about 0.8% flavonoids based on the total dry weight of the E. arvense herb preparation, wherein the total flavonoids are expressed as isoquercetrin equivalents.

In one embodiment, the E. arvense herb preparation is standardized to organic silicon content by a solvent extraction process using raw material with a silicon content that met a minimum silicon requirement, e.g., 3% silicon. In one embodiment, the E. arvense herb preparation of the herb-containing composition of the invention is derived from the stems of the E. arvense herb and standardized for silica content, i.e., E. arvense stem extract preparation. Briefly, stem parts of the E. arvense herb were removed from the plant and dried. They were then measured for a minimum of 2.5% silicon content via HPLC analysis before being accepted for the extraction process. An extract was obtained using 65%(v/v) ethanol/water extraction solvent. The extract was concentrated to a ratio of approximately 4:1. The extract was then tested again for minimum 3% silicon content via HPLC. The final extract dry concentrate appeared as a fine brown powder with a characteristic odor and taste. In another embodiment, the E. arvense herb preparation is standardized to organic silicon by a solvent extraction process. Briefly, stem parts of the E. arvense herb were removed from the plant and dried. Morphological examination of the starting biomass (this includes both microscopic and macroscopic characteristics) ensured the correct species is being used (e.g., an authenticated voucher specimen was stored on file for species identification). An extract was obtained using hot water (between about 50⁰C and about 100⁰C) as a solvent. The extract was concentrated to a ratio of approximately 5:1. The extract was then dried. The extract was tested for a minimum of approximately 3% silicon content via UV-Vis Spectrophotometry (silicon dioxide is used as a reference substance). If the extract fell outside the desired standards above, it was titrated with a dried extract that had undergone the same process as above. The final extract dry concentrate appeared as a yellow-brown colored powder.

In one embodiment, the E. arvense herb preparation of the herb-containing composition of the invention is derived from the stems of the E. arvense herb and standardized for total flavonoid content, i.e., E. arvense stem extract preparation.

In another embodiment, the E. arvense herb preparation is standardized to flavonoid (expressed as isoquercetrin) content by a solvent extraction process. Briefly, stem parts of the E. arvense herb were removed from the plant and dried. They were then identified by TLC. (isoquercetrin is used as reference substance). Morphological examination of the starting biomass (this included both microscopic and macroscopic characteristics) ensured the correct species was being used (e.g., an authenticated voucher specimen was stored on file for species identification). An extract was obtained using hot water (between about 50⁰C and about 100"C) as a solvent. The extract was concentrated to a ratio of approximately 5:1. The extract was then dried. The extract was tested for a minimum of approximately 0.01% isoquercetrin via UV-Vis Spectrophotometry (isoquercetrin was used as reference substance). If the extract fell outside the desired standards above, it was titrated with a dried extract that had undergone the same process as above. The final extract dry concentrate appeared as a yellow-brown colored powder. In one embodiment, the E. arvense herb preparation was standardized to organic silicon content and flavonoid content (expressed as isoquercetrin) using the methods described above.

In one aspect of the present invention, the herb-containing composition of the invention contains C. nurvala stem/bark extract and E. arvense herb preparation and colloidal anhydrous silica. The additional silicon assists with urogenital tissue support, strengthening and firmness. In one embodiment, the herb-containing composition of the invention contains from about 10 mg dry weight equivalents to about 71 mg dry weight equivalents of total silicon per oral dosage unit. In another embodiment, the herb-containing composition of the invention contains from about 15 mg dry weight equivalents to about 45 mg dry weight equivalents of total silicon per oral dosage unit. In another embodiment, the herb-containing composition of the invention contains from about 28 mg dry weight equivalents to about 34 mg dry weight equivalents of total silicon per oral dosage unit.

In another aspect of the invention, the herb-containing composition of the invention contains phosphorous. In one embodiment, the herb-containing composition of the invention contains from about 5 mg dry weight equivalents of phosphorous to about 60 mg dry weight equivalents of phosphorous per oral dosage unit. In another embodiment, the herb-containing composition of the invention contains from about 10 mg dry weight equivalents of phosphorous to about 50 mg dry weight equivalents of phosphorous per oral dosage unit. In another embodiment, the herb-containing composition of the invention contains from about 20 mg dry weight equivalents of phosphorous to about 30 mg dry weight equivalents of phosphorous per oral dosage unit.

In another aspect of the invention, the herb-containing composition of the invention contains calcium. In one embodiment, the herb-containing composition of the invention contains from about 1 mg dry weight equivalents of calcium to about 30 mg dry weight equivalents of calcium per oral dosage unit. In another embodiment, the herb-containing composition of the invention contains from about 5 mg dry weight equivalents of calcium to about 25 mg dry weight equivalents of calcium per oral dosage unit. In another embodiment, the herb-containing composition of the invention contains from about 10 mg dry weight equivalents of calcium to about 20 mg dry weight equivalents of calcium per oral dosage unit.

In another aspect of the invention, the herb-containing composition of the invention contains magnesium. In one embodiment, the herb-containing composition of the invention contains from about 1 mg dry weight equivalents of magnesium to about 30 mg dry weight equivalents of magnesium per oral dosage unit. In another embodiment, the herb-containing composition of the invention contains from about 5 mg dry weight equivalents of magnesium to about 25 mg dry weight equivalents of magnesium per oral dosage unit. In another embodiment, the herb-containing composition of the invention contains from about 10 mg dry weight equivalents of magnesium to about 20 mg dry weight equivalents of magnesium per oral dosage unit.

In one embodiment, the invention provides a herb-containing composition, comprising: a C. nurvala stem/bark preparation present at a concentration at least about 1 ,000 mg dry weight equivalents per oral dosage unit; an E. arvense stem extract preparation present at a concentration of at least about 670 mg dry weight equivalents per oral dosage unit; a total Saw palmetto {Serenoa repens/serrυlata) concentration of at least about 1,070 mg dry weight equivalent; a total concentration of at least about 2.92 g Tomato (Lycopersicon esculentum), standardized to contain at least about 500 μg Lycopene; a total concentration of at least about 5 mg zinc; a total concentration of at least about 8 μg dry weight equivalents selenium. In one embodiment, the invention provides a method a method of treating or preventing a disorder of the prostate, wherein the oral dosage unit is administered to the subject in an amount sufficient to treat or prevent the disorder of the prostate. In another embodiment , the oral dosage unit is administered to the subject at least once per day. In another embodiment, the oral dosage unit is administered to the subject between two and five times per day.

In one embodiment, the herb-containing composition further comprises a Serenoa repens/serrulata (Saw palmetto) berry preparation, wherein Serenoa repens/serrυlata is present at a concentration of at least about 107 mg of extract standardized to contain approx 85% fatty acids and sterols per oral dosage unit. In another embodiment, the herb-containing composition is co-administered to the subject with a second composition comprising the Serenoa repens/serrulata berry preparation, which may be administered contemporaneously with, or before, or after the herb-containing composition is administered to the subject.

In one embodiment, the herb-containing composition further comprises a Pygeum africanum bark preparation, wherein Pygeum africanum is present at a concentration of at least about 100 mg dry weight, standardized to contain 2.5 mg phytosterols per oral dosage unit. In another embodiment, the herb-containing composition is co-administered to the subject with a second composition comprising the Pygeum africanum bark preparation, which may be administered contemporaneously with, or before, or after the herb-containing composition is administered to the subject. In one embodiment, the herb-containing composition further comprises an Urtica dioica (stinging nettles) root preparation, wherein Urtica dioica is present at a concentration of at least about 100 mg extract per oral dosage unit. In another embodiment, the herb-containing composition is co-administered to the subject with a second composition comprising the Urtica dioica root preparation, which may be administered contemporaneously with, or before, or after the herb-containing composition is administered to the subject.

In one embodiment, the herb-containing composition further comprises Lycopersicon esculentum (tomato) fruit, wherein Lycopersicon escυlentum is present at a concentration of at least about 333 mg, standardized to contain 0.1 mg of Lycopene, per oral dosage unit. In another embodiment, the herb-containing composition is co-administered to the subject with a second composition comprising Lycopersicon escυlentum, which may be administered contemporaneously with, or before, or after the herb-containing composition is administered to the subject.

In one embodiment, the herb-containing composition further comprises a Curcubita pepo (pumpkin seed) seed preparation, wherein Curcubita pepo is present at a concentration of at least about 10 g dry weight per oral dosage unit. In one embodiment, the herb-containing composition further comprises a Curcubita pepo (pumpkin seed) seed preparation, wherein Curcubita pepo is present at a concentration from at least about 0.1 g dry weight per oral dosage unit to about 1 g dry weight per oral dosage unit. In one embodiment, the herb-containing composition further comprises a Curcubita pepo (pumpkin seed) seed preparation, wherein Curcubita pepo is present at a concentration from at least about 0.1 g dry weight per oral dosage unit to about 5 g dry weight per oral dosage unit. In one embodiment, the herb-containing composition further comprises a Curcubita pepo (pumpkin seed) seed preparation, wherein Curcubita pepo is present at a concentration from at least about 5 g dry weight per oral dosage unit to about 10 g dry weight per oral dosage unit. In another embodiment, the herb-containing composition is co-administered to the subject with a second composition comprising the Curcubita pepo seed preparation, which may be administered contemporaneously with, or before, or after the herb-containing composition is administered to the subject.

In one embodiment, the herb-containing composition further comprises zinc, wherein the zinc is present at a concentration of at least about 3 mg dry weight equivalents per oral dosage unit. In another embodiment, the herb-containing composition is co-administered to the subject with a second composition comprising zinc, which may be administered contemporaneously with, or before, or after the herb-containing composition is administered to the subject.

In one embodiment, the herb-containing composition further comprises copper, wherein copper is present at a concentration of at least about 1 mg dry weight equivalents per oral dosage unit. In another embodiment, the herb-containing composition is co-administered to the subject with a second composition comprising copper, which may be administered contemporaneously with, or before, or after the herb-containing composition is administered to the subject.

In one embodiment, the herb-containing composition further comprises selenium, wherein selenium is present at a concentration of at least about 5 μg dry weight equivalents per oral dosage unit. In another embodiment, the herb-containing composition is co-administered to the subject with a second composition comprising selenium, which may be administered contemporaneously with, or before, or after the herb-containing composition is administered to the subject.

In one embodiment, the herb-containing composition further comprises cholecalciferol (Vitamin D3), wherein cholecalciferol is present at a concentration of at least about 200 IU dry weight equivalents per oral dosage unit. In another embodiment, the herb-containing composition is co-administered to the subject with a second composition comprising cholecalciferol, which may be administered contemporaneously with, or before, or after the herb-containing composition is administered to the subject. In one embodiment, the herb-containing composition further comprises vitamin E, wherein vitamin E is present at a concentration of at least about 50 IU dry weight equivalents per oral dosage unit. In another embodiment, the herb-containing composition is co-administered to the subject with a second composition comprising vitamin E, which may be administered contemporaneously with, or before, or after the herb-containing composition is administered to the subject.

In one embodiment, the herb-containing composition further comprises vitamin B6, wherein vitamin B6 is present at a concentration of at least about 25 mg dry weight equivalents per oral dosage unit. In another embodiment, the herb-containing composition is co-administered to the subject with a second composition comprising vitamin B6, which may be administered contemporaneously with, or before, or after the herb-containing composition is administered to the subject.

In one embodiment, the herb-containing composition further comprises vitamin C, wherein vitamin C is present at a concentration of at least about 100 mg dry weight equivalents per oral dosage unit. In another embodiment, the herb-containing composition is co-administered to the subject with a second composition comprising vitamin C, which may be administered contemporaneously with, or before, or after the herb-containing composition is administered to the subject.

In one embodiment, the herb-containing composition further comprises glutamic acid (as l-glutamic acid), wherein glutamic acid is present at a concentration of at least about 200 mg dry weight equivalents per oral dosage unit. In another embodiment, the herb-containing composition is co-administered to the subject with a second composition comprising glutamic acid, which may be administered contemporaneously with, or before, or after the herb-containing composition is administered to the subject.

In one embodiment, the herb-containing composition further comprises glycine, wherein glycine is present at a concentration of at least about 200 mg dry weight equivalents per oral dosage unit. In another embodiment, the herb-containing composition is co-administered to the subject with a second composition comprising glycine, which may be administered contemporaneously with, or before, or after the herb-containing composition is administered to the subject. In one embodiment, the herb-containing composition further comprises alanine, wherein alanine is present at a concentration of at least about 200 mg dry weight equivalents per oral dosage unit. In another embodiment, the herb-containing composition is co-administered to the subject with a second composition comprising alanine, which may be administered contemporaneously with, or before, or after the herb-containing composition is administered to the subject.

In another embodiment, the herb-containing composition of the invention is used in a cream. In one embodiment, the herb-containing composition of the invention contains from about 1 mg to about 100 mg dry weight equivalents C. nurvala stem/bark extract per gram of cream. In another embodiment, the herb-containing composition of the invention contains from about 10 mg to about 60 mg dry weight equivalents C. nurvala stem/bark extract per gram of cream. In another embodiment, the herb-containing composition of the invention contains from about 40 mg to about 60 mg dry weight equivalents C. nurvala stem/bark extract per gram of cream.

In another embodiment, the herb-containing composition of the invention contains from about 1 mg to about 60 mg dry weight equivalents E. arvense herb per gram of cream. In another embodiment, the herb-containing composition of the invention contains from about 5 mg to about 40 mg dry weight equivalents E. arvense herb per gram of cream. In another embodiment, the herb-containing composition of the invention contains from about 10 mg to about 30 mg dry weight equivalents E. arvense herb per gram of cream.

In another embodiment of the invention, the herb-containing composition contains orange oil. In one embodiment, the herb-containing composition of the invention contains from about

1 mg to about 30 mg orange oil per gram of cream. In another embodiment, the herb-containing composition of the invention contains from about 5 mg to about 25 mg dry orange oil per gram of cream. In another embodiment, the herb-containing composition of the invention contains from about 8 mg to about 12 mg orange oil per gram of cream. In one embodiment of the invention, the herb-containing composition contains Juniperus virginiana (Cedarwood) stem essential oil. In one embodiment, the herb-containing composition of the invention contains from about 1 μg to about 1 ,000 μg J. virginiana stem essential oil per gram of cream. In another embodiment, the herb-containing composition of the invention contains from about from about 250 μg to about 750 μg J. virginiana stem essential oil per gram of cream. In another embodiment, the herb-containing composition of the invention contains from about 400 μg to about 600 μg J. virginiana stem essential oil per gram of cream.

In one embodiment of the invention, the herb-containing composition contains Myrrh oil. In one embodiment, the herb-containing composition of the invention contains from about 1 μg to about 1 ,000 μg Myrrh oil per gram of cream. In another embodiment, the herb-containing composition of the invention contains from about from about 250 μg to about 750 μg Myrrh oil per gram of cream. In another embodiment, the herb-containing composition of the invention contains from about 400 μg to about 600 μg Myrrh oil per gram of cream.

In one embodiment of the invention, the herb-containing composition contains Orange flower oil. In one embodiment, the herb-containing composition of the invention contains from about 1 μg to about 1 ,000 μg Orange flower oil per gram of cream. In another embodiment, the herb-containing composition of the invention contains from about from about 250 μg to about 750 μg Orange flower oil per gram of cream. In another embodiment, the herb-containing composition of the invention contains from about 400 μg to about 600 μg Orange flower oil per gram of cream.

In one embodiment of the invention, the herb-containing composition contains Cupressus sempervirens (Cypress) leaf oil. In one embodiment, the herb-containing composition of the invention contains from about 1 μg to about 1,000 μg C sempervirens leaf oil per gram of cream. In another embodiment, the herb-containing composition of the invention contains from about from about 50 μg to about 500 μg C. sempervirens leaf oil per gram of cream. In another embodiment, the herb-containing composition of the invention contains from about 75 μg to about 125 μg C. sempervirens leaf oil per gram of cream.

In another embodiment of the invention, the herb-containing composition contains d-alpha- tocopheryl acetate (Natural Vitamin E). In one embodiment of the invention the herb-containing composition of the invention contains d-alpha-tocopheryl acetate. In one embodiment, the herb- containing composition of the invention contains from about 0.1 mg to about 25 mg d-alpha- tocopheryl acetate per gram of cream. In another embodiment, the herb-containing composition of the invention contains from about 1 mg to about 10 mg dry d-alpha-tocopheryl acetate per gram of cream. In another embodiment, the herb-containing composition of the invention contains from about 4 mg to about 6 mg d-alpha-tocopheryl acetate per gram of cream. In another embodiment of the invention, the herb-containing composition contains diazolidinylurea. In one embodiment of the invention, the herb-containing composition of the invention contains diazolidinylurea. In one embodiment, the herb-containing composition of the invention contains from about 0.1 mg to about 10 mg diazolidinylurea per gram of cream. In another embodiment, the herb-containing composition of the invention contains from about 1 mg to about 5 mg dry diazolidinylurea per gram of cream. In another embodiment, the herb- containing composition of the invention contains from about 3 mg to about 3.5 mg diazolidinylurea per gram of cream.

In another embodiment of the invention, the herb-containing composition contains hydroxybenzoates. In one embodiment, the herb-containing composition of the invention contains hydroxybenzoates. In one embodiment, the herb-containing composition of the invention contains from about 0.1 mg to about 5 mg hydroxybenzoates per gram of cream. In another embodiment, the herb-containing composition of the invention contains from about 0.5 mg to about 3 mg dry hydroxybenzoates per gram of cream. In another embodiment, the herb-containing composition of the invention contains from about 1 mg to about 2 mg hydroxybenzoates per gram of cream.

In another embodiment of the invention, the herb-containing composition contains extracts of C. nurvala stem/bark extract; and E. arvense leaf; Orange oil; J. virginiana stem; Myrrh oil; Orange flower oil; C. sempervirens leaf; d-alpha-tocopheryl acetate; diazolidinylurea; and hydroxybenzoates. MEDICINAL PROPERTIES AND USES OF COMPOSITIONS OF THE INVENTION

The present invention provides herb-containing compositions useful in a method of prophylaxis or treatment of disorders of the prostate, e.g., enlarged prostate or benign prostatic hyperplasia (BPH)₁ prostatitis, and prostatic intraepithelial neoplasia. It is thought that the primary active ingredients present in both the Crateva and Equisetum are the saponins and plant sterols. Crateva contains flavonoids, glucosinolates and the plant sterol, lupeol, while Equisetum contains the mineral, silica, flavonoids (isoquercetin, luteolin, and kaempferol) and the saponin, equisetin. Nadkarni K.M. et al., Indian Materia. Medica. Bombay Popular Prakashan; British Herbal Pharmacopeia. Publ: British Herbal Medicine Association 1983; Bone K. Clinical Applications of Ayurvedic and Chinese Herbs. Monographs for the western herbal practitioner. Phytotherapy Press, Warwick, QId, Australia 1997; The German Commission E Monographs, 1998; D'Agostino M. et al., Boll. Soc. Ital. Biol. Sper, 30;60(12):2241-5 (1984); Pengelly A. The constituents of medicinal plants: an introduction to the chemistry and therapeutics of herbal medicine. Sunflower Herbal 2^nd Edition, Merriwa, NSW, Australia, 1996; Lakshmi V. et al., Planta Medica, 32: 214-216 (1977). The herb-containing compositions of the present invention are useful in the prevention and treatment of incontinence, benign prostatic hyperplasia, and urinary incontinence. Crateva administration produces a marked relief of symptoms of frequency, incontinence, pain and retention of urine in men with hypotonic bladder as a result of benign prostatic hyperplasia. Deshpande PJ. et al., Indian J. Med. Res., 76 (Suppl):46-53 (1982). Crateva acts to increase the tone of the bladder and the expulsive force of urine, thereby helping effective evacuation. Deshpande P.J. et al., Indian J. Med. Res., 76 (Suppl):46-53 (1982). Cystometric studies analyzed in this paper also show that Crateva normalizes the tone of the urinary bladder and significantly decreases residual urine volume. The herb-containing compositions of the present invention, therefore, are useful in the prevention and treatment of urinary incontinence.

These results are also supported by animal studies where Crateva has been shown to increase the tone of both smooth and skeletal muscle in vitro. Das P.K. et al., J. Res. Ind. Med., 9:49 (1974). Animal studies show that 40 days of treatment with Crateva resulted in hypertonic curves of the urinary bladder when compared to initial curves. Das P.K. et al., J. Res. Ind. Med., 9:49 (1974).

Equisetum is rich in silicic acid and silicates. Silica supports the regeneration of connective tissue. Chevallier, A., The Encyclopedia of Medicinal Plants, (Horn V. and Weil, C, Eds.) Dorling Kindersley Ltd., London (1996). The present invention provides herb-containing compositions useful, therefore in the prophylaxis or treatment of disorders of the urogenital system, e.g., urinary incontinence, enuresis (e.g., bed-wetting), benign prostatic hyperplasia, urinary calculi, cystitis, and UTIs.

Isoquercetin, found in Equisetum, is known to have anti-inflammatory effects via inhibition of inflammatory prostaglandins, although Crateva is thought to produce anti-inflammatory effects via a different mechanism. D'Agostino M. et al.. Boll. Soc. Ital. Biol. Sper, 30;60(12):2241-5 (1984); Geetha T. et al.. Gen. Pharmacol., 32(4):495-7 (1999). The positive effect on chronic urinary tract infections is most likely a combination of anti-bacterial and anti-inflammatory actions.

Cypress is documented as an antispasmodic, astringent, antiseptic, deodorant, diuretic and tonic that may promote venous circulation to the kidneys and bladder area, improve bladder tone and assist with urinary incontinence and enuresis. Tisserand and Balacs, Essential Oil Safety. A Guide for Health Care Professionals. Churchill Livingstone, U. K., 1995; 28-29, 31 , 33- 34; Valnet, J. The Practice of Aromatherapy. Saffron Walden, The C. W. Daniel Company, Essex, England, 1980; 120-121, Holmes, P. The Energetics of Western Herbs. Artemis Press, Boulder, Colorado, USA, 1989; 567-569, 792; Damian, P & K. Aromatherapy Scent and Psyche. Healing Arts Press, Rochester, Vermont, Canada, 1995; 187-188; Price, S. The Aromatherapy Workbook. Thorsons (Harper Collins), California, USA, 1993; 67; Chidell, L. Aromatherapy. A Definitive Guide to Essential Oils. Hodder and Stoughton Ltd, Kent. UK, 1992; 23-24, 80-81; Keller, E. The Compete Home Guide to Aromatherapy. H J Kramer, Inc. Tiburon, California, USA. 1991; 178-179.

Recent literature describes Myrrh as an astringent and antiseptic that produces a soothing effect on mucous membranes of the urinary system and promotes healing of tissues. Battaglia, S. The Complete Guide to Aromatherapy. The Perfect Potion Pty Ltd, Virginia, Brisbane, QId, Australia, 1995; 110-113, 116, 150-151 , 158-159. 182-183, 184-185, 187; Lawless, J. The Encyclopaedia of Essential Oils. (1992) Element Books for Jacaranda Wiley, Ltd, Australia, 1992; 76-77, 88-89, 135-136. Orange and Neroli are documented as having anti-spasmodic, antiseptic and deodorant effects. 6, 10; Sheppard-Hanger. The Aromatherapy Practitioner Manual. Aquarius Publishing, Willetton, Western Australia, 1995; 183; Sellar, W. The Directory of Essential Oils. Saffron Walden, The CW. Daniel Company. Essex, England, 1992; 50-51, 106-107; Keller, E. The Compete Home Guide to Aromatherapy. H J Kramer, Inc. Tiburon, California, USA, 1991 ; 178-179.

The herb-containing compositions of the present invention are useful in the prevention and treatment of disorders of the prostate, e.g., benign prostatic hyperplasia. Essential oils are also recommended for male reproductive health, indicating a possible effect on the prostate in men. Battaglia, S. The Complete Guide to Aromatherapy. The Perfect Potion Pty Ltd, Virginia, Brisbane, QId, Australia, 1995; 110-113, 116, 150-151 , 158-159, 182-183, 184-185, 187; Price. S. Practical Aromatherapy. Thorsons, Harper Collins Publishers, California, U.S., 1983; 157-8, 170- 171 , 174, 185; Lawless, J. The Encyclopaedia of Essential Oils. (1992) Element Books for Jacaranda Wiley, Ltd, Australia, 1992; 76-77, 88-89, 135-136; Valnet, J. The Practice of Aromatherapy. Saffron Walden, The C. W. Daniel Company, Essex, England, 1980; 120-121.

Certain drugs commonly prescribed for urinary incontinence, such as oxybutynin hydrochloride, inhibit the muscarinic action of acetylcholine on smooth muscle, producing a direct antispasmodic action, that is, they relax the detrusor muscle. Tapp A. J. S. et al., Brit. J.

Obstetrics and Gynecology, ; 97: 521-6 (1990). This antispasmodic effect is desired over the anticholinergic effect of drugs previously used for patients with urinary incontinence. The antispasmodic effect of these essential oils, whilst not provided in more specific detail, may also be producing an action similar to currently prescribed drug medications. Herbal diuretics are documented as increasing blood flow through the kidneys without resorption at the distal tubule of the nephron and associated loss of electrolytes (apart from potassium), as is the case with more sophisticated modern drug diuretics. Mills and Bone, Principles and Practice of Phytotherapy. Churchill Livingstone, 2000;35, 220-222. Also, diuresis often does not result from herbal diuretic use. Mills and Bone, Principles and Practice of Phytotherapy. Churchill Livingstone, 2000;35, 220-222. It may be that these herbal essential oils largely stimulate the blood flow to the kidneys resulting in an increase or greater efficiency in the production of urine. This effect, when combined with complete emptying of the bladder when voiding, may minimize the volume of urine lost through continual leakage.

Serenoa repens/serrulata (Saw palmetto) is a herbal product used in the treatment of symptoms related to benign prostatic hyperplasia. The active component is found in the fruit of the American dwarf palm tree. Studies have demonstrated the effectiveness of saw palmetto in reducing symptoms associated with benign prostatic hyperplasia. Serenoa seems to have multiple methods of action including the inhibition of 5 alpha-reductase and interference with binding of dihydrotestosterone (DHT) to androgen receptors in prostate cells. See, Plosker G. Serenoa repens: a review of its pharmocology and therapeutic efficacy in benign prostatic hyperplasia. Drugs Aging, 9(5): 379 (1996); Briley M. ef a/., Inhibitory effect of Permixon on testosterone 5a reductase activity of the rat ventral prostate. Br. J. Pharmacol. 83:401 P (1984); Marks L. S. ef a/., Tissue effects of saw palmetto and finasteride: use of biopsy cores for in situ quantification of prostatic androgens. Urology, 57:999-1005 (2001); Marks L.S. er a/. Effects of a saw palmetto herbal blend in men with symptomatic benign prostatic hyperplasia. J. Urol., 163:1451-56 (2000).

Pygeum africanum (Pygeum) is a large evergreen that grows in the high plateaus of southern Africa. Pygeum extracts have an antimitogenic effect on prostate cancer cells and benign prostatic hyperplasia epithelial cells. Such effect is associated with the inhibition of the mitogenic action of Pygeum, and it is accompanied by a decrease of cells entering the S Phase of the cell cycle. See, Santa Maria Margalef A. ef a/., Antimitogenic effect of Pygeum africanum extracts on human prostatic cancer cell lines and explants from benign prostatic hyperplasia. Arch. Esp. Urol., 56(4):369-78 (2003). In clinical trials of BPH patients, Pygeum was shown to reduce nocturnal urinary frequency and significantly improvement urinary flow and volume. Breza J. Efficacy and accepability of Pygeum africanum extract in the treatment of benign prostatic hyperplasia. Curr. Med. Res. Opin., 14(3):127 (1998); Barlet A. Efficacy of Pygeum africanum extract in the medical therapy of urination disorders due to benign prostatic hyperplasia. Wien. KMm. Woechenschr., 102(22): 667 (1990).

Urtica dioica (stinging nettle) is a perennial plant commonly found in the shady moist areas of forests. Urtica dioica contains active sterols stigmast-4-en-3-one, stigmasterol and campesterol. Urtica dioica has been found to inhibit the enzyme activity related to BPH and subsequently suppress prostate-cell metabolism and growth. Hirano T., Effects of stinging nettle root extracts and their steroidal components on the Na+, K(+)-ATPase of benign prostatic hyperplasia. Planta. Med., 60(1 ):30 (1994).

Lycopersicon esculentum (tomato) is a carotenoid, and is present in human serum, liver, adrenal glands, lungs, prostate, colon and skin at higher levels than other carotenoids. Lycopene has been found to possess antioxidant and antiproliferative properties in animal and in vitro studies. Research studies suggest that high levels of lycopene consumption have been associated with long-term protection of prostate health. See, Giovannucci E. and Clinton S. K., Tomatoes, lycopene, and prostate cancer. Proc. Soc. Exp. Biol. Med. 218(2):129-139 (1998); Giovannucci, E., Tomatoes, tomato-based products, lycopene, and cancer: review of the epidemiologic literature. J. Natl. Cancer Inst., 91(4):317-331 (1999); Huang HY, et al., Prospective study of antioxidant micron utrients in the blood and the risk of developing prostate cancer. Am. J. Epidemiol., 157(4):335-44 (2003).

Curcubita pepo (pumkin seed) extract contains phytosterols, curcubitin and selenium. Clinical studies have shown that a remarkable reduction in urinary frequency related to BPH during the day and night-time can be achieved. Urinary flow rate is also increased and residual urine is reduced. See, Schneider HJ, et al., Treatment of benign prostatic hyperplasia. Fortschr. Med.113:37-40 (1995). The phytosterols in pumpkin seeds are thought to act either by inhibiting DHT or by anti-inflammatory action. Stoff JA. and Clouatre D., The Prostate Miracle: New Natural Therapies That Can Save Your Life (Kensington Publishing Corp., 2000). The minerals zinc, copper, and selenium are antioxidants that are useful for treating disorders of the prostate. Studies have shown that zinc deficiency results in prostate enlargement. See, Fair WR. and Hβston W., Prostate inflammation linked to zinc shortage. Prevention, June: 113 (1977). Zinc concentration is found to be higher in the prostate gland than in other human tissues. However, patients with BPH or prostate cancer had significantly lower levels of zinc than did normal healthy men. A daily zinc supplement totaling 50 to 100 milligrams is frequently recommended to help shrink an enlarged prostate. Zaichick V., Zinc in the human prostate gland. Int. Urol. Nephrol., 29(5): 565 (1997). Copper plays a major role in antioxidant enzyme systems that are helpful for maintaining a healthy prostate. Klevay LM., Lack of a recommended dietary allowance for copper may be hazardous to your health. J. Am. Coll. Nutr. 17(4): 322-6 (1998). Regarding selenium, researchers at Johns Hopkins School of Hygiene and Public Health found that high levels of selenium and vitamin E (alpha-tocopherol and gamma- tocopherol) were effective in the prevention of prostate cancer. Helzlsouer KJ. et al., Association Between σ-Tocopherol, κ-Tocopherol, Selenium, and Subsequent Prostate Cancer, J. Natl. Cancer Inst, 92:2018-2023 (2000). Vitamins D3, E, B6, and C are useful for treating disorders of the prostate. Low blood levels of vitamin D in men correlate with increased risk of prostate cancer incidence. Miller GJ, Vitamin D and prostate cancer: biologic interactions and clinical potentials. Cancer Metastasis Rev. 17(4):353-60 (1998); Corder EH, et al., Vitamin D and prostate cancer: a prediagnostic study with stored sera. Cancer Epidemiol. Biomark. Prev., 2:467-472 (1993). Vitamin E is a powerful antioxidant capable of protecting cells from lipid peroxidation. The action of lipid peroxidation is a vital factor in the process of chronic inflammation of the prostate when antioxidant defenses have fallen. Burton G., Vitamin E application of the principles of physical organic chemistry to the exploration of its structure and function. Ace. Chem. Res., 19:194 (1986); Tarasov N., Correction of abnormal lipid peroxidation in the treatment of chronic prostatitis. Urol. Nβfrol. (Mosk.), Jan- Feb(1 ): 38 (1998). Supplementing with Vitamin E (d alpha-tocopherol) has been shown to reduce both inflammation of BPH and incidence of prostate malignancies. Heinonen O., Prostate cancer and supplementation with alpha-tocopherol and beta-carotene. J. Natl. Cancer Inst., 90(6):40 (1998). Research suggests that vitamin B6 reduces levels of prolactin hormone in men. This decreases the amount of testosterone hormone that is converted to dihydrotestosterone (DHT). It is understood that this decreases the likelihood of developing prostate disorders like BPH. Costello LC and Franklin RB, Effect of prolactin on the prostate. Prostate, 24(3):162-66 (1994). Vitamin C is associated with a 23% decrease in the risk of prostate cancer development. Kristal AR, et al., Vitamin and mineral supplement use is associated with reduced risk of prostate cancer. Cancer Epidemiol. Biomarkers Prev., 8:887-892 (1999).

Glutamic acid, glycine, and alanine are amino acids useful in the treatment of prostate disorders. A study showed that after four weeks, a preparation comprising the three amino acids helped to reduce prostate swelling and alleviate symptoms of urinary discomfort. See, Okada S., Clinical application of amino acid preparation for nonspecific prostatitis. Hinyokika Kiyo, 31(1 ): 179 (1985). An early study found that these amino acids effective in reducing symptoms of BPH and helped reduce the duration of the condition. See, Cuervo Blanco E., Clinical study of a phytosterol extract of Prunus arborea and 3 amino acids: glycine, alanine and glutamic acid. Arch. Esp. Urol., 31(1): 97 (1978).

PHARMACEUTICAL COMPOSITIONS AND FORMULATIONS

The herb-containing compositions of the present invention can be used alone or further formulated with pharmaceutically acceptable compositions, vehicles, or adjuvants with a favorable delivery profile, i.e., suitable for delivery to a subject. Such compositions typically comprise the herb-containing composition of the invention and a pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal compositions, isotonic and absorption delaying compositions, and the like, compatible with pharmaceutical administration. Suitable carriers are described in the most recent edition of Remington's Pharmaceutical Sciences, a standard reference text in the field, which is incorporated herein by reference. Preferred examples of such carriers or diluents include, but are not limited to, water, saline, Ringer's solutions, dextrose solution, and 5% human serum albumin. The use of such media and compositions for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or composition is incompatible with the active composition, use thereof in the compositions is contemplated. Supplementary active compositions can also be incorporated into the compositions.

A pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration. Examples of routes of administration include, e.g., oral; transdermal (i.e., topical), and transmucosal administration. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.

Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules, caplets or compressed into tablets. For the purpose of oral therapeutic administration, the herb-containing composition of the invention can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the composition in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding compositions, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compositions of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating composition such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening composition such as sucrose or saccharin; or a flavoring composition such as peppermint, methyl salicylate, or orange flavoring. The herb- containing compositions of the present invention can also be formulated as a topical cream for transdermal or transmucosal administration.

In one embodiment, the herb-containing compositions of the invention are prepared with carriers that will protect the composition against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, pofyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc.

The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

The invention is further defined by reference to the following examples, which are not meant to limit the scope of the present invention. It will be apparent to those skilled in the art that many modifications, both to the materials and methods, may be practiced without departing from the purpose and interest of the invention. EXAMPLES

Example 1 Clinical Trial of a Herb-Containing Natural Therapeutic Cream for Urinary Incontinence

GENERAL Studies were conducted to investigate the effectiveness of a herb-containing natural therapeutic bladder control cream in relieving urinary incontinence (hereinafter, "bladder control cream" or bladder control cream test preparation). The bladder control cream tested) was a natural herb-containing cream preparation. The test preparation contained primarily essential oil herbal actives, e.g., essential oils of Citrus sinensis (orange) oil, Juniperus virgiπiana (Virginia cedarwood) stem oil, Commiphora myrrha (Myrrh) oil, Citrus aurantium (Neroli or Orange flower) oil, and Cupressus sempervirens (Cypress) leaf, and was formulated in accordance with the principles of essential oil administration. Battaglia, S., In: The Complete Guide to Aromatherapy. The Perfect Potion Pty Ltd, Virginia, Brisbane, QId, Australia, pp. 110-113; 116; 150-151; 158- 159; 182-183; 184-185; 187 (1995); Chidell, L., In Aromatherapy. A Definitive Guide to Essential Oils. Hodder and Stoughton Ltd. Kent, UK, pp. 23-24; 80-81 (1992); Keller, E., In: The Complete Home Guide to Aromatherapy, H J Kramer, Inc. Tiburon, California, USA, pp. 178-179 (1991).

MATERIALS AND METHODS Study Design

The study was conducted according to the TGA's "Guidelines for Good Clinical Research Practice (GCRP) in Australia". The study was approved by the Australian College of Natural Medicine Ethics Committee. The interviews were conducted at the Naturopathic Clinic at the Australian College of Natural Medicine, Brisbane. Thirteen (13) women experiencing symptoms of urge incontinence and/or stress incontinence were recruited through newspaper advertisements. Three (3) women withdrew from the study for personal reasons within the first few weeks. The remaining 10 women completed the three months of the study. Women experiencing urinary incontinence on a regular basis were considered eligible for inclusion in the study if they met the following criteria:

They had not undergone recent surgery particularly hysterectomy or prolapse repair (within the last 12 months); They had not recently undergone childbirth (within the last 12 months);

They were not using any medicine for incontinence symptoms in the last month; They did not have any serious health conditions such as diabetes mellitus, heart disease, pancreatic, hepatic disease or chronic inflammatory conditions;

They were not currently being treated for psychotic disturbances; and They did not suffer from skin disorders that are affected by transdermal applications. Women were asked to maintain current dietary patterns but were not given any advice regarding diet during the study. The exercise patterns of the participants were also noted, with women engaged in some form of exercise at least three times a week regarded as being active.

Participants were asked to apply five grams of the cream to the body twice daily for a period of three months. The effectiveness of the treatment was assessed using the short versions of the Incontinence Impact Questionnaire (HQ) and the Urogenital Distress Inventory (UDI) prior to commencing treatment (month 0) and each month thereafter (months 1 , 2 and 3). The short version (six questions) of the MQ assesses the impact of incontinence on daily activities, such as household chores, physical activity and social activities. The questions in the UDI relate specifically to the physical aspects of incontinence. All questions are rated on a scale of 0 to 3 (0 = not bothered, 1 = slightly bothered, 2 = moderately bothered, 3 = extremely bothered). Both questionnaires are standardized disease specific questionnaires that provide efficient levels to detect bothersome incontinence in older people. Robinson, et a/., Obstetrics and Gynecology, 91:2, 224-8 (1998). The results of these questionnaires were analyzed using the paired t-test.

Test Preparation

The bladder control cream test preparation was manufactured in accordance with the GMP guidelines by a TGA approved manufacturing site. Each gram of the bladder control cream test preparation contained extracts equivalent dry 30 mg C. nurvala stem/bark extract; and 20 mg E. an/ense (Horsetail) leaf; as well as the essential oils of 10 mg Orange oil; 500 μg J. virginiana (Cedarwood) stem; 500 μg Myrrh oil; 500 μg Orange flower oil; 100 μg C. sempervirens (Cypress) leaf; 5 mg d-alpha-tocopheryl acetate (Natural Vitamin E); 3.3 mg diazolidinylurea; and 1.54 mg total hydroxybenzoates. The essential oils used in this preparation are not known to be toxic, irritating or sensitizing.

RESULTS AND DISCUSSION Eight (8) of the women were aged between 60 and 78, with the other two women being significantly younger, 27 and 42 years. The body mass index (BMI) ranged from 24.4 to 31.9 with an average of 28.5. There was no change in weight in these women over the study period.

All women had given birth to at least one child, the average for the group being 2.0 children. All women had experienced symptoms of stress or urge incontinence for at least 10 years. Three (3) of the women had undergone surgery, either insertion of a sling or prolapse repair. None of the participants were using pelvic floor exercises prior to or during the study.

Prior to commencement of the treatment, all women reported that they were extremely bothered by leakage. The cause of the leakage was often a combination of the feeling of urgency, the result of physical activity or just continuous leakage. The results of the effectiveness of this treatment on the physical symptoms monthly over the study period are presented in Table 1 and Figure 1.

Table 1 : Urogenital Distress Inventory

The study results indicated a significant positive change in the responses concerning leakage relating to urgency and activity. These effects were observed after the initial month on the treatment and continued to improve over the three months. There were also improvements in the area of continual leakage and difficulty emptying bladder, although these only became significant after the full three months of the treatment. It is noteworthy, however, that there were no significant changes in the response to frequency of urination over the three months. None of the women were experiencing pain or discomfort in the lower abdomen or lower region, (responding as "not bothered" throughout the study) and did not suffer from frequent urinary tract infections (which is common amongst incontinence sufferers). There were no significant differences in the responses of the non-active group (n = 5) compared to the active group (n = 5) to the questions in the HQ and UDI.

Most of the women reported that incontinence had a negative impact (by a "moderately bothered" or "severely bothered" response at month 0) on their lifestyle and social activities. Comparison of initial responses with those at month 3 showed significant positive changes in response to household chores, physical recreational activities and feeling frustrated (see Table 2). Table 2: Incontinence impact questionnaire

There was a general, but not significant improvement in quality of life questions regarding social activity and emotional health due to incontinence over the three months. There were no significant changes in the responses regarding the impact of incontinence on entertainment activities or traveling 30 minutes from home during the study. Previous studies demonstrated that incontinence has a negative impact on quality of life.

Peake et a/., Med Anthropol. Q₁ 13(3):267-85 (1999); Association for Continence Advice, Aust. Continence J.; 6(2):15-23 (2000); Robinson et ai. Obstetrics and Gynecology, 91:2, 224-8 (1998). The present study indicated a significant improvement in the control of leakage (due to urgency and physical activity) and bladder emptying after three months of treatment with the bladder control cream test preparation. This effect was independent of diet and exercise patterns. It was also noteworthy that this positive response occurred in the absence of specific pelvic exercises.

These results indicated that improvement in physical symptoms was associated with improved self-confidence and ability to function on a daily basis. The formulation of the essential oils in the bladder control cream test preparation appeared to target the urinary system and promote better control over urination. The bladder control cream test preparation may act on the muscles of the pelvic floor, sphincter or bladder wall itself. The absorption of astringent essential oils of the bladder control cream test preparation may be minimal but may promote an antisecretory effect on mucous membranes or a 'toning' effect. Mills and Bone, In Principles and Practice of Phytotherapy. Churchill Livingstone, 35, pp. 220-222 (2000). In combination, the astringent and diuretic actions of the bladder control cream test preparation may produce a 'regulation' or 'normalization' of urine flow, improving control of urination, without producing diuresis.

A notable result in Table 1 was the dramatic decrease in "Leakage due to feeling or urgency." This significant positive change in the responses concerning urge incontinence (OAB wet") indicates that the formulation may be useful for treating overactive bladder (OAB) in general. Both OAB wet" and "OAB dry" are caused by the sudden, involuntary contraction of the muscle in the wall of the urinary bladder, which produce a sudden feeling or urgency to urinate.

Example 2 Clinical Trial of Herb-Containing Natural Therapeutic Tablet for Urinary Incontinence GENERAL

Studies were conducted to investigate the effectiveness of a herb-containing natural therapeutic bladder control preparation in relieving urinary incontinence (hereinafter, "bladder control preparation" or "bladder control test preparation"). Steels, E., Seipel, T. and Rao, A., Australian Continence Journal (2002). The bladder control test preparation was a natural herb- containing preparation formulated as a tablet. Each tablet contained extracts equivalent dry: C. nurvala stem/bark extract (3,000 mg) 3 g, E. arvense (Horsetail) herb (1,500 mg) 1.5 g and Magnesium phosphate 70 mg, Calcium hydrogen phosphate 70 mg, equiv. Calcium 16.3 mg, Magnesium 14.5 mg, Phosphorous 24.9 mg. Contains maltodextrin.

MATERIALS AND METHODS Study Design

Eight (8) women experiencing symptoms of urge incontinence and/or stress incontinence on a regular basis were recruited through newspaper advertisements. All women met the following criteria:

(a) had not undergone recent surgery particularly hysterectomy or prolapse repair within the last 12 months,

(b) did not have any serious health conditions such as diabetes mellitus, heart disease, pancreatic disease, hepatic disease or chronic inflammatory conditions,

(c) were not currently being treated for psychotic disturbances, and

(d) did not use any medicine for incontinence symptoms in the last month prior to commencement of the study.

None of the participants were engaging in the specific pelvic exercises to improve muscle tone prior to the study, although they were aware of them.

The treatment protocol consisted of two tablets twice daily (equivalent to 12 g Crateva and 6 g Equisetum daily) over a period of 12 weeks. The efficacy of the treatment was assessed using the short versions of the Incontinence Impact Questionnaire (HQ) and the Urogenital

Distress Inventory (UDI) prior to commencing treatment (month 0) and each month thereafter (months 1 , 2 and 3). The short version (six questions) of the MQ assesses the impact of incontinence on daily activities, such as household chores, physical activity and social activities. The questions in the UDI relate specifically to the physical aspects of incontinence. All questions are rated on a scale of 0 to 3 (0 = not bothered, 1 = slightly bothered, 2 = moderately bothered, 3 = extremely bothered). Both questionnaires are standardized disease specific questionnaires used to detect bothersome incontinence in older people. Robinson, D. et al., Obstetrics and Gynecology, 91:2, 224-8 (1998).

The study group consisted of eight women. Seven of the participants were aged between 54 and 65, with one participant being 20 years of age. The average age of the study group was 50 years. Six of the participants had given birth to at least two children, while two participants had not had children. The results of these questionnaires were analyzed using the paired t-test.

Test Preparation

The bladder control test preparation tablets were manufactured in accordance with the GMP guidelines by a TGA approved manufacturing site. Each tablet contained the herbs, C. nurvala stem/bark extract and E. arvense leaf and the minerals, magnesium phosphate and calcium phosphate. The study was conducted according to the TGA's "Guidelines for Good Clinical Research Practice (GCRP) in Australia". The study was approved by the Australian College of Natural Medicine Ethics Committee. The interviews were conducted at the Naturopathic Clinic at the Australian College of Natural Medicine, Brisbane.

RESULTS AND DISCUSSION

The effectiveness of the bladder control test preparation on the physical symptoms is summarized in Table 3 and Figure 2. Prior to treatment, 80% of the participants reported that they were bothered by leakage related to activity. This was reduced to 40% after 3 months of treatment (Figure 2). Similar responses were observed for leakage due to urgency (60% to 35%), frequent urination reduced (70% to 48%), difficulty emptying bladder (50% to 25%). Prior to treatment, 50% of participants experienced pain or discomfort prior to treatment, but none reported these symptoms after 2 months of treatment. There was a 25% reduction in the number of women responding to small amounts of leakage (75% to 50%) after treatment. Analysis (paired t-test) of the data showed that there was a significant positive change in the perceptions of frequency of urination after a month of treatment (p = 0.040), and this continued in a gradual manner over the duration of the study (p = 0.24 at 2 months, p = 0.013 at 3 months). There was a significant positive change in perceptions regarding leakage relating to urgency (p = 0.024), leakage due to activity (p = 0.031), and difficulty emptying bladder (p = 0.052) after 3 months of treatment. Again, positive effects were seen after the first initial month of treatment.

There was a positive trend in the responses regarding the small amounts of leakage during the study but these were not significant. A significant positive response in relation to pain or discomfort in the lower abdomen or lower region (p= 0.025) was also observed after 2 months of treatment.

Table 3: Urogenital Distress Inventory

The responses to the Incontinence Impact Questionnaire are presented in Table 6 and Figure 3. The results showed that participants felt that incontinence had a significant negative impact on their quality of life, as assessed by a range of 50-70% "bothered score" for the seven parameters of the HQ (Figure 3). This was reduced significantly (to a range of 10-25%) for all parameters, except the question regarding physical recreation, in which there was little variation between month 0 and month 3.

Analysis (paired t-test) of the data showed that there was an improvement in the perception of the effect of incontinence on lifestyle and social activities, indicated by positive changes in response to social activities (p = 0.04), entertainment activities (p = 0.017), emotional health (p = 0.025) and travel >30 minutes from home (p = 0.052), feeling frustrated (p = 0.007) after 3 months of treatment. There was no change in the responses regarding household chores or physical recreation (Table 4).

Table 4: Incontinence impact questionnaire

The results from this study indicate a significant (at p>0.05) improvement in the control of leakage (due to urgency and physical activity), bladder emptying and pain or discomfort after three months of treatment with the bladder control test preparation. These results are supported by reports of earlier studies showing that treatment with Crateva relieved incontinence, pain and retention of urine in men. Deshpande P.J. ef al., Indian J. Med. Res., 76 (Suppl.):46-53 (1982).

Acetylcholine is the primary excitatory neurotransmitter involved in bladder emptying. Certain drugs commonly prescribed for urinary incontinence, such as oxybutynin hydrochloride, inhibit the muscarinic action of acetylcholine on smooth muscle, producing a direct antispasmodic action. These drugs relax the detrusor muscle. Wada Y. et al., Arch. Int. Pharmacodyn. Ther., 330(1 ):76-89 (1995); Tapp A.J.S. et al., Brit. J. Obstetrics Gynecology, 97: 521-6 (1990). These medications also produce unwanted anticholinergic effects, such as dry mouth, blurred vision and constipation. Pathak AS, Aboseif SR. Overactive Bladder: Drug therapy versus nerve stimulation. Nat Clin Pract Urol, 2(7):310-311 , 2005. There are currently no medications that specifically target incontinence symptoms without having side effects elsewhere in the body. The mechanisms whereby these herbal drugs exert these effects is unknown, although it is interesting to note that there were no side effects reported from the treatment, as seen with the anticholinergic drugs. Example 3 Clinical Trial of a Herb-Containing Natural Therapeutic Tablet (Formula 2) with Standardized Silicon Content for Use in the Prevention and Treatment of Urinary Incontinence and Overactive Bladder (OAB) GENERAL

Studies were conducted to investigate the effectiveness of a herb-containing natural therapeutic bladder control preparation in relieving urinary incontinence and overactive bladder (i.e., bladder control test preparation) for oral administration. These studies were designed and performed as generally described above in Example 2 and further detailed below. The bladder control test preparation was a natural herb-containing preparation formulated as a tablet.

Silicon has been identified as a contributor to the biological activity of E. arvense herb. Non-standardized preparations of E. arvense herb generally contain silicon from about 1.2% to about 6.9% silicon based on total dry weight of preparation. In one aspect of the present invention, it has been determined that batch variation in the silicon content of E. arvense herb preparations can have negative effects on the biological activity of the composition of the present invention. This problem has been resolved by the present invention by providing an E. arvense herb preparation with optimized, standardized silicon content. Accordingly, in one embodiment of the invention, the silicon content of the E. arvense herb preparation in the herb-containing preparation of the invention is standardized. The use of a standardized preparation E. arvense herb is advantageous because the inter-batch variation of silicon is reduced, thus the composition of the present invention yields more consistent preventative or therapeutic effect.

MATERIALS AND METHODS Test Preparation

The bladder control test preparation tablets were manufactured in accordance with the GMP guidelines by a TGA approved manufacturing site. Each tablet contained the herbs, C. nurvala stem/bark extract and E. arvense stem extract and the minerals, magnesium phosphate and calcium phosphate and silicon. For example, each tablet contained dry weight equivalents as follows: C. nurvala stem/bark extract (3,000 mg), E. arvense (Horsetail) stem extract preparation with a standardized silicon content of 3% based on the total dry weight of the E. arvense stem extract preparation (1,500 mg), colloidal anhydrous silica (50.3 mg), magnesium phosphate 70 mg, calcium hydrogen phosphate 70 mg, equiv. calcium 16.3 mg, magnesium

14.5 mg, phosphorous 24.9 mg. Each tablet contained 41.6 mg dry weight equivalents of total silicon per tablet. Each tablet contained some maltodextrin. Study Design

Human subjects (males and females) experiencing symptoms of overactive bladder, urge incontinence and/or stress incontinence on a regular basis were recruited through newspaper advertisements. All human subjects met the following criteria: (a) had not undergone recent surgery particularly hysterectomy or prolapse repair within the last 12 months,

(b) did not have any serious health conditions such as diabetes mellitus, heart disease, pancreatic disease or hepatic disease,

(c) did not use any medicine for incontinence symptoms in the last month prior to commencement of the study.

None of the participants were engaging in the specific pelvic exercises to improve muscle tone prior to the study.

The treatment protocol consisted of human test subjects ingesting two tablets of the bladder control test preparation twice daily over a period of 12 weeks. The efficacy of the treatment was assessed by recording average daily and nightly frequency of urination and the short versions of the Incontinence Impact Questionnaire (MQ) and the Urogenital Distress Inventory (UDI) prior to commencing treatment (month 0) and each month thereafter (months 1, 2, and 3). The questions in the UDI related specifically to the physical aspects of incontinence as detailed below in Table 5. Table 5: Urogenital Distress Inventory

Do you experience, and if so, how much are you bothered by:

Frequent urination

Leakage due to feeling or urgency

Leakage due to activity, coughing, sneezing

Small amounts of leakage (drops)

Difficulty empting bladder

Pain or discomfort in lower abdominal or genital area

The short version (six questions) of the MQ assessed the impact of incontinence on daily activities, such as household chores, physical activity and social activities as summarized below in Table 6. Table 6: Incontinence impact questionnaire

Has urine leakage affected the following:

Household chores

Physical recreation

Entertainment activities

Travel >30 min from home

Social activities

Emotional health

Feeling frustrated

All questions were rated on a scale of 0 to 3 (0 = not bothered, 1 = slightly bothered,

2 = moderately bothered, 3 = extremely bothered). Both questionnaires were standardized disease specific questionnaires used to detect bothersome incontinence in older people.

Robinson, D. ef a/., Obstetrics and Gynecology, 91 :2, 224-8 (1998). Also analyzed was the average frequency of urination during the day and night at month 0,1,2 and 3, these results were also compared using a paired t-test.

The results of these questionnaires were analyzed using the paired t-test. A positive improvement was defined as a statistically significant difference, i.e., p value ≤0.05, in a parameter measuring the physical aspects of incontinence or the physical or social activities of test subjects receiving the bladder control test preparation when compared to the same parameter in human test subjects prior to receiving the bladder control test preparation. A positive improvement in any parameter relating to the physical aspects of incontinence or the physical or social activities of human test subjects receiving the bladder control test preparation when compared to the same parameter in human test subjects prior to receiving the bladder control test preparation demonstrates that the bladder control test preparation is useful to prevent or treat a urogenital system disorder in a human subject, e.g., urinary incontinence; overactive bladder; enuresis; benign prostatic hyperplasia; urinary calculi; cystitis; and urinary tract infection. RESULTS AND DISCUSSION Demographics

There were nine participants completing the study, three males and six females, with an average age of 52 years (range 41-72 years).

Frequency of Urination During The Day The results show that the frequency of urination during the day reduced steadily during the

3 months of treatment. The number of times participants needed to empty the bladder reduced from 14 (prior to treatment), to 10 times per day (after 1 month), 8.3 times per day (after 2 months) and further reduced to 6.6 times per day by 3 months. This is shown to be a significant reduction between month 0 and subsequent months (p = 0.02 at month 2; p = 0.01 at month 3). Frequency of Nocturia

The results show that this treatment was effective in reducing the number of times participants needed to empty the bladder at night. There was a gradual reduction in awakenings from 2.7 times per night initially to 2.0 times, 1.4 times and 1.0 times per night (month 1, 2 and 3 respectively). The results of the t-test showed there was a significant reduction in frequency between month 0 and month 2 (p = 0.047) and month 3 (p = 0.024).

The majority of participants in the study reported nocturia as a major symptom and one of the reasons for participating in this study. The overall improvement in Quality of Life (discussed below) appeared directly linked to the fact that they were experiencing longer periods of uninterrupted sleep (notes from individual files).

The Urogenital Distress Inventory

The symptoms experienced by most participants (Figure 4) were: frequent urination, (approximately 89%). leakage due to urgency affecting 78% of the participants, and small amounts of leakage 67%. Other symptoms included leakage due to activity (56%), difficulty emptying bladder (44%) and pain or discomfort (33%). The results presented in Figure 5, (as the average bothered responses) indicate that symptoms in all of the categories reduced after one month of treatment and continued to decrease over the next 2 months.

The results of the questionnaire were analyzed using the paired t-test. A significant positive change in the frequency of urination occurred after 2 months and remained significant at month 3 of treatment (p = 0.009, 0.011 respectively). Other significant reductions in symptoms occurred by month 2 and continued to be significant at month 3 were: leakage due to urgency (p = 0.028, 0.016 respectively)., difficulty emptying bladder (p = 0.035. 0.081 respectively) , and small amounts of leakage (p = 0.022, 0.043 respectively).

Incontinence Impact Questionnaire The activities that showed to be most impacted on by incontinence and OAB (Figure 6) were: Physical recreation and Travel greater than 30 minutes from home (approximately 89%). Household chores, Social activities. Emotional health and Feeling frustrated were experienced by 78% of participants and Entertainment activities were affected in 67% of participants.

The results presented in Figure 7, (as the average bothered responses) clearly show that quality of Life (assessed through difficulty in doing daily and social activities as well as emotional health and feelings of frustration) are adversely affected by having the symptoms of Incontinence. On average, participants were less bothered (and most confident) in these activities within 4 weeks of treatment, with continual improvement reported throughout the rest of the study. The results of the questionnaire were analyzed using the paired t-test. There was an improvement in the perception of the effect of incontinence on lifestyle and social activities, indicated by positive changes in response to all questions by the end of the study. Significant improvements in all questions occurred at month 2 (see Table 7). The significant positive effect for questions regarding emotional health and feeling frustrated indicate that the treatment is associated with improvements in quality of life.

Participants were also asked at the month 3 interview if the treatment had improved their Quality of Life. Overall, 67% reported an improvement in QOL. These results clearly indicate that there is a significant improvement in QOL for participants that experience relief or a reduction in the severity in the symptoms of urinary incontinence and OAB, including frequency, nocturia, urgency and bladder discomfort.

Table 7 - Results of paired t-test (p values) Urinary Distress Inventory and Incontinence Impact Questionnaire

Urinary Distress Inventory

Leakage Small amounts Difficulty

Frequent Leakage due related to of leakage emptying Pain or t-test results Urination to urgency activity (drops) bladder discomfort

Month 0 vs 1 0.051 0.050 0.347 0.104 0.035 0.169

Month 0 vs 2 0.009 0.028 0.104 0.022 0.035 0.081

Month 0 vs 3 0.011 0.016 0.139 0.043 0.081 0.225

Incontinence Impact Questionnaire

Travel greater

Household Physical Entertainment than 30 min Social Emotional Feeling

T-test results chores recreation activities from home activities health frustrated

Month 0 vs 1 0.195 0.195 0.051 0.272 0.051 0.104 0.195

Month 0 vs 2 0.050 0.043 0.023 0.023 0.023 0.013 0.028

Month 0 vs 3 0.052 0.052 0.023 0.021 0.023 0.007 0.016

CONCLUSION

The results of this study indicate that Formula 2 preparation, using E. arvense standardized for silicon content, was a suitable and effective treatment for both men and women, It was effective in reducing symptoms of urinary incontinence and OAB, including frequency, nocturia, urgency and bladder discomfort. Symptom relief occurred after 4 weeks of treatment, with the severity of symptoms reducing further, especially in the 8-12 week period of using the treatment. The treatment was not associated with major adverse reactions.

Formula 2, with E. arvense standardised for silica content, showed comparable results to the original tablet formula, however results generally occurred faster with severity of symptoms (bothered rating) decreasing more consistently after 1 month of treatment. Also at month 3 of treatment, less participants were experiencing the urinary distress symptoms compared to month 3 results of Formula 1. This study shows that Formula 2, containing E. arvense standardized for silica content, is more effective than a similar formula with no standardization for silicon.

Example 4 Clinical Trial of a Herb-Containing Natural Therapeutic Tablet with

Standardized Silicon Content and Flavonoid Content (Formula 3) for Use in the Prevention and Treatment of Urinary Incontinence and

Overactive Bladder (OAB).

GENERAL

Studies were conducted to investigate the effectiveness of a herb-containing natural therapeutic bladder control preparation in relieving urinary incontinence and OAB {i.e., bladder control test preparation) for oral administration. These studies were designed and performed as generally described above in Example 2 and Example 3 and further detailed below. The bladder control test preparation was a natural herb-containing preparation formulated as a tablet.

Silicon has been identified as a contributor to the biological activity of E. arvense herb. In addition to silicon, E. arvense contains about 5 percent of a saponin, designated equisetonin, and several flavone glycosides (a./c.a., flavonoids) including isoquercetrin, galuteolin, and equisetrin. Isoquercetrin (a.k.a, isoquercetrin; Quercetin 3-O-β-D-glucopyranoside; 4H-1-Benzopyran-4-one, 2-(3,4-dihydroxy-phenyl)-3-(β-D-glucofυranosyloxy)-5_I7-dihydroxy-). Flavonoids, e.g., isoquercetrin, may have important pharmacological properties. In certain aspects of the present invention, it has been determined that batch variation in the silicon content and/or flavonoid content expressed as isoquercetrin of E. arvense herb preparations can have negative effects on the biological activity of the composition of the present invention. This problem has been resolved by the present invention by providing E. arvense herb preparations with optimized, standardized silicon content and flavonoid content expressed as isoquercetrin. The study assessed the efficacy of the improved formulation in preventing and treating the symptoms of urinary incontinence and OAB.

MATERIALS AND METHODS Test Preparation

The bladder control test preparation tablets were manufactured in accordance with the GMP guidelines by a TGA approved manufacturing site. Each tablet contained the herbs, C. nurvata stem/bark extract and E. arvense stem extract and the minerals, magnesium phosphate and calcium phosphate and silicon. For example, each tablet contained dry weight equivalents as follows: C. nurvala stem/bark extract (3,000 mg), E. arvense (Horsetail) stem extract preparation with a standardized silicon content of 3% and a standardized flavonoid content of 0.8% (expressed as isoquercetrin) based on the total dry weight of the E. arvense stem extract preparation (1 ,500 mg), colloidal anhydrous silica (50.3 mg), magnesium phosphate 70 mg, calcium hydrogen phosphate 70 mg, equiv. calcium 16.3 mg, magnesium 14.5 mg, phosphorous 24.9 mg. Each tablet contained 60.8 mg dry weight equivalents of total silicon per tablet. Each tablet contained some maltodextrin.

Study Design Human subjects experiencing symptoms of urge incontinence and/or stress incontinence on a regular basis were recruited through newspaper advertisements. All human subjects met the following criteria:

(a) having not undergone recent surgery particularly hysterectomy or prolapse repair within the last 12 months, (b) did not have any serious health conditions such as diabetes mellitus, heart disease, pancreatic disease, or hepatic disease, (c) did not use any medicine for incontinence symptoms in the last month prior to commencement of the study.

The treatment protocol consisted of human test subjects ingesting two tablets of the bladder control test preparation twice daily over a period of 12 weeks. The efficacy of the treatment was assessed by recording average daily and nightly frequency of urination and using the short versions of the Incontinence Impact Questionnaire (UQ) and the Urogenital Distress Inventory (UDI) prior to commencing treatment (month 0) and each month thereafter (months 1 , 2, and 3). The questions in the UDI related specifically to the physical aspects of incontinence as detailed below in Table 8.

Table 8: Urogenital Distress Inventory

Do you experience, and if so, how much are you bothered by:

Frequent urination

Leakage due to feeling or urgency

Leakage due to activity, coughing, sneezing

Small amounts of leakage (drops)

Difficulty empting bladder

Pain or discomfort in lower abdominal or genital area

The short version (six questions) of the HQ assesses the impact of incontinence on daily activities, such as household chores, physical activity and social activities as summarized below in Table 9. Table 9: Incontinence impact questionnaire

Has urine leakage affected the foliowing:

Household chores

Physical recreation

Entertainment activities

Travel >30 min from home

Social activities

Emotional health

Feeling frustrated

All questions were rated on a scale of 0 to 3 (0 = not bothered, 1 = slightly bothered, 2 = moderately bothered, 3 = extremely bothered). Both questionnaires were standardized disease specific questionnaires used to detect bothersome incontinence in older people. Robinson, D. et al., Obstetrics and Gynecology, 91 :2, 224-8 (1998). Also analyzed was the average frequency of urination during the day and night at month 0,1 ,2 and 3, these results were also compared using a paired t-test.

The results of these questionnaires were analyzed using the paired t-test. A positive improvement was defined as a statistically significant difference, i.e., p value <0.05, in a parameter measuring the physical aspects of incontinence or the physical or social activities of test subjects receiving the bladder control test preparation when compared to the same parameter in human test subjects prior to receiving the bladder control test preparation. A positive improvement in any parameter relating to the physical aspects of incontinence or the physical or social activities of human test subjects receiving the bladder control test preparation when compared to the same parameter in human test subjects prior to receiving the bladder control test preparation demonstrates that the bladder control test preparation is useful to prevent or treat a urogenital system disorder in a human subject, e.g., urinary incontinence; overactive bladder; enuresis; benign prostatic hyperplasia; urinary calculi; cystitis; and urinary tract infection.

RESULTS AND DISCUSSION Demographics

There were 10 participants (two males and eight women) completing the study with an average age of 65.9 years (range 49-71 years).

Frequency of Urination During The Day

The results demonstrated that the average frequency of urination during the day reduced significantly (p<0.05) during the 3 months of treatment. The number of times participants needed to empty the bladder reduced from 11.5 (prior to treatment), to 8.5 times per day (after 1 month), 6.6 times per day (after 2 months) and further reduced to 6.0 times per day by 3 months. These results were significant at month 1 (p = 0.017) and remained significant throughout the study (p = 0.02 at month 2 and month 3). Frequency of Nocturia

The results demonstrated that this treatment was effective in reducing the number of times participants needed to empty the bladder at night. There was a reduction in awakenings from 2.5 times per night initially to 1.5 times, 0.5 times and 0.5 times per night (month 1, 2, and 3 respectively). This was a significant difference (p<0.05) at month 2 and 3 of treatment. Many of the participants were able to sleep though the night altogether after 2 months of treatment. These results were significant at month 1 (p = 0.063) and remained significant throughout the study (p = 0.007 at month 2; p = 0.03 month 3).

The Urogenital Distress Inventory Symptoms experienced by most participants (Figure 8) were: frequent urination (78%), urgency (78%), small amounts of leakage (67%), and emptying bladder (67%). The other symptoms were reported as less of a problem, were: leakage due to activity affecting 44% of the participants, with only 33% reporting pain in the abdominal region. The results presented in Figure 9, (as the average bothered rating) indicate that all symptoms were reduced one month of treatment and continued to reduce over the next 2 months.

The results of the questionnaire were analyzed using the paired t-test. There was a significant positive change after 2 months of treatment which continued at month 3 for the following symptoms: a feeling of being less bothered by leakage due to urgency (p = 0.011 , 0.017 respectively), small amounts of leakage (p = 0.011, 0.015 respectively), and difficulty in empting bladder (p = 0.024, 0.045 respectively). A significant positive change in the frequency of urination occurred after month 3 (p = 0.009).

Incontinence Impact Questionnaire

The activities that showed to be most impacted on by incontinence and OAB (Figure 10) were: Entertainment activities and feeling frustrated (80%), physical recreation, and travel greater than 30 minutes from home, household chores, and social activities were experienced by 70% of participants and emotional health was affected in 60% of participants.

The results presented in Figure 11 , as the average bothered responses, clearly show that Quality of Life (assessed through difficulty in doing daily and social activities as well as emotional health and feelings of frustration) are adversely affected by having the symptoms of Incontinence. Participants were less bothered in most of these activities within 1 month of treatment, except for household chores (which reduced bothered rating at month 2) with continual improvement reported throughout the rest of the study.

The results of the questionnaire were analyzed using the paired t-test (Table 10). There was an improvement in the perception of the effect of incontinence on lifestyle and social activities, indicated by positive changes in response to all questions (except household chores) by the end of the study. Significant improvements in travel greater than 30 min were reported after the first month of treatment, with further positive effects observed at month 2 and month 3 (p = 0.037, 0.010 and 0.015 respectively). After 2 and 3 months of treatment, there was a significant improvement in confidence in emotional health (p = 0.081 and 0.029, respectively), and feeling frustrated (p = 0.001 and 0.001 , respectively), entertainment (p = 0.015 and 0.004, respectively), and physical recreation (p = 0.022 and 0.012, respectively), which indicates that the treatment is associated with improvements in quality of life.

Participants were also asked, at the month 3 interview, if the treatment had improved their Quality of Life. Overall, 70% reported an improvement in QOL These results clearly indicate that there is a significant improvement in QOL for participants that experience relief or a reduction in the severity in the symptoms of urinary incontinence and OAB, including frequency, nocturia, urgency and bladder discomfort.

Table 10 — Results of paired t-test (p values) Urinary Distress Inventory and Incontinence Impact Questionnaire Urinary Distress Inventory

Leakage Leakage Small amounts Difficulty

Frequent due to related to of leakage emptying Pain or

T-test results Urination urgency activity (drops) bladder discomfort

Month 0 vs 1 0.591 0.096 0.168 0.015 0.168 0.081

Month 0 vs 2 0.051 0.011 0.081 0.011 0.024 0.096

Month 0 vs 3 0.009 0.017 0.269 0.015 0.045 0.089

Incontinence Impact Questionnaire

Travel greater than

Household Physical Entertainment 30 min from Social Emotional Feeling

T-test results chores recreation activities home activities health frustrated

Month 0 vs 1 0.726 0.081 0.104 0.037 0.193 0.509 0.104

Month 0 vs 2 0.343 0.022 0.015 0.010 0.052 0.081 0.001

Month 0 vs 3 0.132 0.012 0.004 0.015 0.011 0.029 0.001

CONCLUSION

The results of this study indicate that Formula 3, containing E. arvense standardised for silica and flavonoid content, was effective in reducing all symptoms of urinary incontinence and OAB₁ including frequency, nocturia, urgency and bladder discomfort. Symptom relief occurred after 4 weeks of treatment, with the severity of symptoms reducing further, especially in the 4-8 week period of using treatment. Formula 3 was suitable and effective treatment for both men and women and was not associated with major adverse reactions.

Accordingly, Formula 3 used in this study, demonstrated superior results to both Formula 1 and Formula 2. Formula 3 demonstrated increased effectiveness in reducing all symptoms of urinary incontinence and OAB and results were experienced within a shorter timeframe. This study demonstrated that Formula 3, containing E. arvense standardised for silica and flavonoid content is more effective than both Formula 1 and Formula 2.

Example 5 Comparison of the effectiveness of the different tablet formulations (Formulations 1, 2 and 3) for Use in the Prevention and Treatment of Urinary Incontinence and Overactive Bladder (OAB)

GENERAL

The aim of this study was to compare the efficacy of three of the tablet formulations of the present invention, Formula 1 , Formula 2 and Formula 3, in treating the symptoms of urinary incontinence and OAB by analysing the results of the Incontinence Impact Questionnaire (HQ) and the Urogenital Distress Inventory (UDI) from each of the studies. Formula 1 is a non- standardized formula assessed in Clinical study Example 2; Formula 2 uses an E. arvense extract standardized for silicon and was assessed in Clinical study Example 3; and Formula 3 uses an E. arvense extract standardized for silicon and flavonoid content and was assessed in Clinical study Example 4. Study Design

In order to directly compare the effectiveness of the three different tablet formulations, percent (%) reduction in bothered ratings for both questionnaires were compared. This method of analysis was used for comparison as month 0 (baseline) values in each of the studies varied. The frequency of urination and nocturia were directly assessed in Formula 2 and Formula 3 only. RESULTS AND DISCUSSION

The results from the Urinary Distress Inventory (UDI) indicate that Formula 2 (standardized for silicon content) had a higher effectiveness compared to Formula 1 , specifically in the areas of frequent urination, leakage due to feeling of urgency, small amounts of leakage (drops) and difficulty empting bladder. Formula 3 (standardized for Silicon and flavonoid content) was shown to be the most effective in reducing urinary distress (UDI), specifically frequent urination, leakage due to feeling or urgency, leakage due to activity, coughing, sneezing, small amounts of leakage (drops) and difficulty empting bladder by showing a higher percent reduction in symptom severity (Table 11). All formulations showed at least 75% effectiveness in reducing abdominal pain. However, since less than 40% of participants experienced this symptom at month 0, the results are not considered to be significant. Table 11 - Percent reduction in bothered rating of UDI for Formula 1 ,2 and 3 at month 3

Comparison of the Incontinence Impact Questionnaire (HQ) also indicated that Formula 3 had a better response (shown by reduction in symptoms) to all the QOL questions than Formula 1 and 2.

The number (%) of people experiencing the symptoms at each month was also assessed. The Formula 3 showed increased effectiveness, in that there were less participants experiencing each symptom by 3 months, compared to the previous formulations (Figure 12).

The frequency of urination and nocturia was only assessed in Formula 2 and Formula 3. Comparison of these results indicate that while both formulations were effective in reducing the frequency of urination during the day (by approximately 50%) and the effect was seen by the end of the first 8 weeks of treatment. However, Formula 3 was superior to Formula 2 in reducing nocturia with a 96% reduction in symptoms being observed by month 2 and overall a greater reduction in frequency (96% compared to 63% at month 3) (Table 12).

Table 12 - Percent Decrease in Frequency of Urination

CONCLUSION

The results of this study indicate that all preparations are safe and were not associated with major adverse reactions. All preparations were effective in reducing all symptoms of urinary incontinence and OAB, including frequency, nocturia, urgency and bladder discomfort. All preparations were shown to give symptom relief with the severity of symptom reduction generally being faster and more marked with Formula 2 and Formula 3. Formula 3 was the most effective compared with Formula 2 in reducing nocturia.

In summary, all formulations show effectiveness in treating symptoms of urinary incontinence and OAB. The standardization of the E. arvense for silicon (Formula 2) improved the effectiveness of the original formulation and this was further optimized by standardization of E. arvense for both Silicon and flavonoids (Formula 3). Example 6 Silicon Testing of Formulations Used in Incontinence and Overactive Bladder Trials

GENERAL

Inter-batch variation of silicon content is expected in therapeutic formulations as many excipients contain silicon dioxide, in what is considered a non-absorbable form.

It has been suggested that inter-batch variation in silicon content of the formulations used in the incontinence and overactive bladder trials can result in the level of silicon falling below the therapeutically active silicon level per tablet.

The Formula 1 used in Clinical study Example 2 produced therapeutic effectiveness in relief from symptoms of urinary incontinence. As this formula used a non-standardized Equisetum arvense extract, inter-batch variation in silicon content of this formula is likely and may result in inconsistent effectiveness.

Formula 2 (used in Clinical study Example 3) and Formula 3 (used in Clinical study Example 4) were invented to resolve this problem of potential inter-batch variation and subsequent inconsistent effectiveness. They included an E. arvense extract standardized for silicon content and a consistent quantity of added colloidal anhydrous silica. The testing of all three formulations for silicon content was undertaken to determine the degree of possible inter- batch variation of Formula 1 and to confirm that therapeutic levels of silicon are maintained when using formulations containing E. arvense with standardized silicon content. Various testing methods for measuring silicon content are available and may produce variable results. Therefore the same test method was used for each sample. The ICPMS test method currently listed in the British Pharmacopeia (BP) was used. This method completely destroys all other molecules in a composition, leaving only the silicon which can then be measured against a SiO₂ (silicon dioxide) control. This method measures all silicon and does not differentiate between bioavailable and non-absorbable forms of silicon.

RESULTS

Formula 1 , contains a non-standardized E. arvense extract. Upon testing, this batch of Formula 1 showed a silicon content of 34.0 mg per tablet (each tablet was approximately 1 ,000 mg). A subsequent batch of Formula 1 was tested for silicon content and showed 14.5 mg per tablet (again, each tablet was approximately 1,000 mg). This is an inter-batch variation of approximately 60% and highlights that when using a Horsetail extract that is not standardized for silicon that significant inter-batch variation in silicon content does occur. Inter-batch silicon content variation of this magnitude, and where the content falls below that shown to be effective in earlier research, is expected to reduce therapeutic effectiveness. This was observed with the subsequent batch of Formula 1 containing 14.5 mg of silicon per tablet. This batch produced poorer and inconsistent results when compared to the original production batch of Formula 1 containing 34.0 mg silicon per tablet. (Data not shown)

Formula 2 and Formula 3 both use an E. arvense extract standardized for silicon and a consistent quantity of colloidal anhydrous silica. On testing, Formula 2 and 3 showed a silicon content per tablet of 41.6 mg and 60.8 mg per tablet, respectively (again, each tablet was approximately 1,000 mg). These levels were above the 34.0 mg silicon per tablet, shown in Clinical study Example 2 to be therapeutically effective. As well the variation in silicon content between batches of these two formulations was only 30%, a 50% reduction of the inter-batch variation of Formula 1. It would be expected that inter-batch variation (where the same formula (either Formula 2 or Formula 3) were used) would be minimized even further using these formulations with E. arvense standardized for silicon.

Table 13 - Results of Silicon testing using ICPMS BP Method

It should be noted that total % silicon described in Table 13 includes both bioavailable silicon from the standardized Eqυisetυm arvense extract preparation and silicon from the excipients, which are largely non-bioavailable. The components of a tablet of Formula 2 are summarized in Table 14. According to the present invention, consistent good results are obtained with formulation with standardized Equisetum arvense extract preparation with at least about 3% silicon. In a preferred embodiment, the formulation includes a standardized Equisetum arvense extract preparation with at least about 3% to about 13% silicon. In another preferred embodiment, the formulation includes a standardized Equisetum arvense extract preparation with at least about 5% to about 10% silicon. In yet another preferred embodiment, the formulation includes a standardized Equisetum arvense extract preparation with at least about 6% silicon. Table 14 — Composition of a Formula 2 tablet

CONCLUSION

A consistent preventative or therapeutic effect would be more likely if inter-batch content of silicon in the tested formulae were minimized. The results of testing of different batches of a non- standardized silicon-containing formula (i.e., Formula 1) show inter-batch variation of 60%. Such batch variations are expected to result in inconsistent and reduced preventative and therapeutic effectiveness.

Formula 2 and Formula 3 use E. arvense extracts with standardized silicon contents and a consistent quantity of colloidal anhydrous silica, so consistent silicon content per tablet for each formula are obtained. The variation in silicon content between batches of these two formulations was only 30%, a 50% reduction of the inter-batch variation of Formula 1. It would be expected that inter-batch variation using the same formula (either 2 or 3) would be minimized even further.

By the use of a consistent optimal quantity of standardized silicon content of E. arvense, the bioavailable silicon content of the invention can be standardized per tablet. This avoids negative issues associated with batch variation in bioavailable silicon content.

The invention of Formula 2 and Formula 3, with an optimized, standardized silicon content of E .arvense, minimizes the problem of inter-batch variation in silicon content of formulations. Subsequently a more consistent preventive or therapeutic effect results, as shown in Clinical studies 3, 4 and 5.

Example 7 Clinical Trial of a Herb-Containing Natural Therapeutic Tablet for Use in the Prevention and Treatment of Benign Prostatic Hyperplasia

GENERAL

Studies were conducted to investigate the effectiveness of a herb-containing natural therapeutic preparation in relieving benign prostatic hyperplasia (i.e., prostate control test preparation) for oral administration. The prostate control test preparation is a natural herb- containing preparation formulated as a capsule. MATERIALS AND METHODS Test Preparation

The prostate control test preparation capsules were manufactured in accordance with the GMP guidelines by a TGA approved manufacturing site (TGA's "Guidelines for Good Clinical Research Practices (GCRP) in Australia"). Each capsule contained the herbs, C. nurvala stem/bark extract and E. arvense stem extract. For example, each capsule contains dry weight equivalents as follows: C. nurvala stem/bark extract (1,000 mg) and E. arvense stem extract preparation (670 mg).

Study Design Male human subjects experiencing symptoms of BPH on a regular basis were recruited through newspaper advertisements. All male human subjects met the following criteria:

(a) had not undergone recent prostate surgery within the last 12 months,

(b) did not have any serious health conditions such as diabetes mellitus, heart disease, pancreatic disease, hepatic disease or chronic inflammatory conditions, (c) were not currently being treated for psychotic disturbances,

(d) did not use any medicine for BPH symptoms in the last month prior to commencement of the study, and

(e) were not engaging in the specific pelvic exercises to improve muscle tone prior to the study.

The treatment protocol consisted of human test subjects ingesting 1 capsule of the prostate control test preparation three times daily over a period of 12 weeks.

The efficacy of the treatment was assessed using the frequency of urination and nocturia, the International Prostate Symptom Score (IPSS) and the Urogenital Distress Inventory (UDI) prior to commencing treatment (month 0) and each month thereafter (months 1, 2 and 3). The IPSS gives a rating of the impact of BPH. Both questionnaires are standardized disease specific questionnaires.

The questions in the UDI relate specifically to the physical aspects of incontinence and OAB and their effect on quality of life. All questions are rated on a scale of 0 to 3 (0 = not bothered, 1 = slightly bothered, 2 = moderately bothered, 3 = extremely bothered).

The questions in the UDI relate specifically to the physical aspects of BPH symptoms as detailed below in Table 15.

Table 15: Urogenital Distress Inventory (Do you experience, and if so, how much are you bothered by: I Dribbling after voiding

Feeling that the bladder has not emptied completely after urination Frequent urination, particularly at night

Leakage of urine

Small amounts of leakage (drops) caused by decreased force Pushing or straining to begin urination

Blood in the urine caused by straining to void.

The IPSS consists of seven (7) questions regarding specific symptoms associated with BPH.

The Maximum IPSS is 35 (maximum rating of all questions being 5). Ratings:

0 Not at all,

1 Less than 1 time in 5,

2 Less than half the time,

3 About half the time, 4 More than half the time,

5 Almost always

The IPSS uses the following rating system:

0 - 8 Mild Symptoms;

9 — 19 Moderate Symptoms 20 - 35 Severe Symptoms.

The results of these questionnaires were analyzed using the paired t-test. A positive improvement was defined as a statistically significant difference, i.e., p value <0.05, in a parameter measuring the physical aspects of BPH or the physical or social activities of test subjects receiving the prostate control test preparation when compared to the same parameter in human test subjects prior to receiving the prostate control test preparation. RESULTS AND DISCUSSION Demographics

There were 10 subjects completing the 3 month study. They were aged 42 - 76 years, with a medium age of 59 years.

Daytime Frequency

The average Daytime Urinary Frequency was ranged between 7-12 at Baseline. A significant reduction (p<0.05) was demonstrated by month 2 and continued to improve by month 3. Overall, there was a significant reduction in frequency by the end of the study. This value is comparable to urinary frequency in healthy people.

Nocturia (Night Time Urinary Frequency)

There was a significant reduction in nocturia after one (1 ) month of treatment (p<0.05) and this continued throughout the study. By month 3 the average number of toilet visits per night was below 1.5.

IPSS Total

Subjects reporting a total IPSS of >9 (Moderate/Severe Symptoms) were eligible for study. This study involved 10 subjects all with total IPSS symptom scores at baseline within the moderate symptom level

The average total IPSS score reduced slightly after one (1) month of treatment further reducing significantly at month 2 and 3 (Table 16).

Table 16: Total IPPS Score: Average and % Reduction from Baseline in Symptoms.

After 3 months of treatment the subjects were reclassified according to the IPSS: 8 participants as mild, 11 as moderate and 3 as severe.

Urinary Distress Inventory

The UDI is a standardized disease-specific questionnaire used to detect bothersome incontinence in older people. The question "How much are you bothered' by a symptom assessed Quality Of Life. This is different to the IPSS which asked for specific quantitative data (How often does this symptom occur). There was a significant improvement in Quality of Life, as assessed by UDI. The average bothered rating for each of the 6 questions in the UDI reduced in month 1 and further reduced in month 2 with significant results shown by month 3.

Conclusion In conclusion, there was a significant reduction in prostate related symptoms by month 3 as a result of the Prostate Formulation demonstrating that this formula is useful to prevent or treat a prostate disorder in a human subject, e.g., BPH.

The effects on the bladder (frequency day and night) were the most positive and occurred within the first month. There were gradual improvements in symptoms of urinary flow and a change in the strength of the urinal steam (as assessed by the IPSS).

Example 8 Clinical Trial of a Herb-Containing Natural Therapeutic Tablet in

Combination with Other Compositions for Use in the Prevention and Treatment of Benign Prostatic Hyperplasia

GENERAL Studies were conducted to investigate the effectiveness of a herb-containing natural therapeutic preparation that was administered in combination with other compositions in relieving benign prostatic hyperplasia (i.e., prostate control test preparation) for oral administration. The prostate control test preparation was a natural herb-containing preparation formulated as a capsule. MATERIALS AND METHODS Test Preparation

The prostate control test preparation capsules were manufactured in accordance with the GMP guidelines by a TGA approved manufacturing site (TGA's "Guidelines for Good Clinical Research Practices (GCRP) in Australia"). Each capsule contained the herbs, C. nurvala stem/bark extract and E. arvense stem extract. For example, each capsule contains dry weight equivalents as follows: C. nurvala stem/bark extract (1 ,000 mg) and E. arvense stem extract preparation (670 mg).

Each prostate control test preparation capsule was administered in combination with at least one of the 15 following compositions: (1) Serenoa /serrulata (Saw palmetto) 107mg of extract standardized to contain approx 85% fatty acids and sterols; (2) Pygeum africanum bark 100 mg standardized to contain 2.5 mg phytosterols; (3) Urtica dioica (stinging nettles) root 100 mg; (4) Lycopersicon esculentum (tomato) fruit 2.92 g, standardized to contain 0.5 mg of Lycopeπe; (5) Curcubita pepo (pumpkin seed) seed 10 g; (6) zinc 5 mg; (7) copper 1 mg; (8) selenium 8 μg; (9) cholecalciferol (Vitamin D3) 200 IU; (10) a vitamin E 50 IU dry weight equivalents per oral dosage unit; (11) a vitamin B6 25 mg; (12) vitamin C concentration 100 mg; (13) glutamic acid (as l-glutamic acid) 200 mg; (14) glycine 200 mg; and (15) alanine 200 mg. For example, one or more of these 15 compositions were contained within the prostate control test preparation capsule or were co-administered with the prostate control test preparation capsule. In the case of co-administration, one or more of these 15 compositions were administered to the subject before or after the prostate control test preparation capsule was administered to the subject.

Study Design Male human subjects experiencing symptoms of BPH on a regular basis were recruited through newspaper advertisements. All male human subjects meet the following criteria:

(a) had not undergone recent prostate surgery within the last 12 months,

(e) were not engaging in the specific pelvic exercises to improve muscle tone prior to the study. The treatment protocol consisted of human test subjects ingesting 1 capsule of the prostate control test preparation capsule three times daily over a period of 12 weeks with any other combination as listed above. The efficacy of the treatment was assessed using the frequency of urination and nocturia, the International Prostate Symptom Score (IPSS) and the Urogenital Distress Inventory (UDI) prior to commencing treatment (month 0) and each month thereafter (months 1, 2 and 3). The IPSS gives a rating of the impact of BPH.

The questions in the UDI relate specifically to the physical aspects of BPH symptoms as detailed below in Table 17.

Table 17: Urogenital Distress Inventory

[Do you experience, and if so, how much are you bothered by:

Dribbling after voiding

Feeling that the bladder has not emptied completely after urination

Frequent urination, particularly at night

Leakage of urine

Small amounts of leakage (drops) caused by decreased force

Pushing or straining to begin urination

Blood in the urine caused by straining to void. The results of these questionnaires were analyzed using the paired t-test. A positive improvement was defined as a statistically significant difference, i.e., p value <0.05.

RESULTS AND DISCUSSION

A summary of other compositions take by study participants is shown below in Table 18. Table 18: Summary of other compositions taken by participants

N = 10 (number of participants in study)

Note : Some participants were taking more than 1 other composition Note* Amino acid formulations containing any of the following: L -glutamic acid, glycine, alanine.

Demographics

There were 10 subjects completing the 3 month study using the prostate control test preparation capsule with any other combination specified above. They were aged 47 - 73 years, with a medium age of 64 years. Body weight ranged between 64 — 110 kg, with a medium weight of 89.7 kg. The median Body Mass Index (BMI) was 28.4. The majority (8) of subjects were classified as overweight or obese (BMI >25) with only 2 subjects within the limits for normal body weight (BMI 19.5 - 24.5).

Urinary frequency

The average Daytime Urinary Frequency was 7.3 times at Baseline (range of 3 - 12). There was a significant reduction in frequency after one (1 ) month of treatment, from 7.3 to 6.0 times per day (19% reduction). (This was significant at p<0.05). The trend continued after two (2) months of treatment with an average of 5 visits (or a 21% reduction in day time frequency. After 3 months of treatment, subjects recorded an average daily frequency of 5.0, (corresponding to a 32% reduction in frequency compared to baseline). Overall, there was a significant reduction in frequency.

Nocturia (Night Time Urinary Frequency)

The average Night Time Urinary Frequency was 3.4 times at baseline (range of 1 -9). There was a significant reduction in nocturia after one (1) month of treatment (p<0.05) and this continued throughout the study. The frequency reduced to 2.2 times per night, (a 35% reduction, and range of 1 - 5 times per night). This result was similar to that recorded at two (2) months of treatment with an average of 2.4 visits (or a 29.4% reduction in nocturia, range being 1 — 4 times per night). There was further significant improvement after 3 months of treatment, with subjects recording an average nightly frequency of 1.1 times / night, (corresponding to a 68% reduction in nocturia compared to baseline, and a range of only 0-3 visits / night). There were 5 subjects (50%) reporting a frequency of more than 3 times per night. At the end of the study, all subjects reported frequencies of less than 3 visits per night.

INTERNATIONAL PROSTATE SYMPTOM SCORE (IPSS) Questions and ratings

1. ...had a sensation of not emptying your bladder completely after you finished urinating?

2. ...had to urinate again less than two hours after you finished urinating?

3. ...stopped and started again several times when you urinated?

4. ...found it difficult to postpone urination?

5. ...had a weak urinary stream?

6. ...had to push or strain to begin urination?

7. Over the past month, how many times did you most typically get up to urinate from the time you went to bed at night until the time you got up in the morning?

The Maximum IPSS is 35 (maximum rating of all questions being 5). Ratings:

0 Not at all,

1 Less than 1 time in 5, 2 Less than half the time,

3 About half the time,

4 More than half the time,

5 Almost always

The IPSS uses the following rating system: 0 - 8 Mild Symptoms;

9 - 19 Moderate Symptoms; 20 — 35 Severe Symptoms. IPSS Total - average, average % reduction

Subjects reporting a total IPSS of <9 (Moderate/Severe Symptoms) were eligible for study. This study involved 10 subjects with total IPSS symptom scores at baseline ranging from 12 - 33, with an average rating of 21. Of these, 4 subjects had symptoms classified as having Mild Symptoms (IPSS 9 - 19) and

6 subjects classified as having Severe Symptoms (IPSS 20 - 35). The subjects were reclassified according to the IPSS after 3 months of treatment, with now 5 subjects only experiencing Mild symptoms, 3 experiencing Moderate Symptoms, and only 2 as having Severe Symptoms. All subjects experienced a reduction in symptom severity after 3 months of treatment. The average total IPSS score at Baseline was 21. This reduced slightly after one (1) month of treatment to 15.3, corresponding to a 26.4% reduction in IPSS. After two (2) months of treatment, the average IPSS further reduced to 13.5, corresponding to a 35.1% reduction in IPSS. The overall IPSS results recorded after three (3) months of treatment was 10.7, which corresponded to a 49% reduction in IPSS. These changes at month 1 , 2 and 3 were significant (p<0.05).

Urinary Distress Inventory

The UDI is a standardized disease-specific questionnaire used to detect bothersome incontinence in older people. The question "How much are you bothered" by a symptom is assessing Quality Of Life. This is different to the IPSS which asks for specific quantitative data {How often does this symptom occur).

Table 19: Urinary Distress Inventory

Do you experience, and if so, how much are you bothered by:

1. Frequent urination

2. Leakage due to feeling or urgency

3. Leakage due to activity, coughing, sneezing

4. Small amounts of leakage (drops)

5. Difficulty emptying bladder

6. Pain or discomfort in lower abdominal or genital area

Ratings: 0, No; 1 , slightly; 2, moderately; 3 greatly

The most highly scored symptom was Question 1 ( frequency ). This correlates well with the frequency diary and the IPSS₁ (that indicate that urinary frequency during the day and night is the most commonly observed and most distressing symptom). There was a general improvement, shown by a reduction from 2.4 to 0.8 in average bothered scores (from Moderate/ Severely Bothered to Slightly Bothered) for frequency. The Q5 ( Difficulty emptying bladder ) was also identified as a distressing symptom affecting quality of life, with an average bothered score of 2.0. After month 3 of treatment, there was a significant reduction to 0.5 at Month 3.

The subjects rated the other symptoms, (Q2. 3, 4, 6) as being less bothered by them (Score of >1.5), although these symptoms also improved over the 3 months of the study.

However, together the IPSS and UDI show a significant positive trend of reduction in symptoms and an increase in Quality of Life.

The Quality of Life was assessed using a single question. "If you were to spend the rest of your life with your urinary condition the way it is now, how would you feel about that?" 0. Delighted

1. Pleased

2. Mostly satisfied

3. Mixed - about equally satisfied and dissatisfied

4. Mostly dissatisfied 5. Unhappy

6. Terrible

The average rating prior to treatment was Mostly Dissatisfied (rating of 4.4 with a range of 2 - 6). This reduced slightly at month 1 (still mostly dissatisfied, average 3.9). This reduced further at Month 2 to Mixed (an average 3.2). However, at Month 3, subjects recorded an average of 2.4, representing a change from Mostly Satisfied at Month 3.

The positive improvement in a range of parameters relating to the physical aspects of BPH and the physical or social activities of human test subjects receiving the prostate control test preparation when compared to the same parameter in human test subjects prior to receiving the prostate control test preparation demonstrated that the prostate control test preparation is useful to prevent or treat a prostate disorder in a human subject, e.g., BPH, prostatitis, and prostatic intraepithelial neoplasia.

Example 9 Clinical Trial of a Herbal Preparation Containing Crateva, Horsetail and Saw palmetto for the treatment of Benign Prostate Hypertrophy (BPH) and for Overactive Bladder (OAB) and Urinary Incontinence (Ul) associated with BPH

GENERAL

Studies were conducted to investigate the effectiveness of a herb-containing therapeutic preparation (hereinafter called, BPH preparation or BPH test preparation) in treating the urologic symptoms associated with BPH in men aged between 35 and 80 years. The BPH test preparation was a natural herb-containing preparation formulated as a capsule. Each capsule contained extracts equivalent dry: Crateva. nurvala stem/bark extract 1.0 g, Equisetum arvensβ (Horsetail) herb, 670 mg, Serenoa serrulata (Saw palmetto) fruit 1.07 g, Lycoperscion esculentum (Tomato) fruit 2.92 g, Zinc, 5 mg and Selenium, 8 μg. MATERIALS AND METHODS Study Design

Men (aged between 35 and 80 years) experiencing symptoms of clinically diagnosed BPH were recruited through newspaper advertisements in Brisbane, Australia. All met the following criteria: (a) persons whose life expectancy was not severely limited due to pre-existing malignancy or other disease (<1 year).

(b) no recent urogenital surgery (< 3 months).

(c) patients were not enrolled in another investigational study

(d) no bladder biopsy / cystoscopy + biopsy (<30 days) nor Chronic persistent local pathology {e.g., interstitial cystitis, bladder stones)

(e) were not currently being treated for psychotic disturbances, and

(f) did not use any medicine for incontinence symptoms in the last month prior to commencement of the study.

The treatment protocol consisted of one capsule three times daily (equivalent to 3 g C. nurvala, 2.01 g E. arvense, 3.21 g S. serrulata, 8.76 g L. esculentum , 15 mg Zinc and 24 μg Selenium daily) over a period of 12 weeks.

The efficacy of the treatment was assessed using the frequency of urination and nocturia, the International Prostate Symptom Score (IPSS) and the Urogenital Distress Inventory (UDI) prior to commencing treatment (month 0) and each month thereafter (months 1 , 2 and 3). The IPSS gives a rating of the impact of BPH. Both questionnaires are standardized disease specific questionnaires.

The questions in the UDI relate specifically to the physical aspects of incontinence and OAB and their effect on quality of life. All questions are rated on a scale of 0 to 3 (0 = not bothered, 1 = slightly bothered, 2 = moderately bothered, 3 = extremely bothered). The results of these questionnaires are analyzed using the paired t-test. A positive improvement was defined as a statistically significant difference, i.e., p value <0.05, in a parameter measuring the physical aspects of BPH or the physical or social activities of test subjects receiving the prostate control test preparation when compared to the same parameter in human test subjects prior to receiving the prostate control test preparation. Test Preparation

The BPH test preparation capsules were manufactured in accordance with the Good Manufacturing Practice (GMP) guidelines by a TGA approved manufacturing site. Each capsule contained the herbs, C. nurvala, E. arvense, S. serrulate, L esculentum, and the minerals, Zinc and Selenium. The study was conducted according to the TGA's "Guidelines for Good Clinical Research Practice (GCRP) in Australia". The study was approved by the Australian College of Natural Medicine Ethics Committee. The interviews were conducted at the Naturopathic Clinic at the Australian College of Natural Medicine, Brisbane.

RESULTS AND DISCUSSION Demographics

There were 23 subjects completing the 3 month study. They were aged 39 - 79 years, with a medium age of 63 years. Body weight ranged between 60 - 104 kg, with a medium weight of 83.7 kg. The median Body Mass Index (BMI) was 26.7. There were 14 subjects classified as overweight or obese (BMI >25) with 9 subjects within the limits for normal body weight (BMI 19.5 - 24.5).

Statistically, there was no Correlation between Age and Symptom Severity (using the total IPSS for Severity rating). Statistically, there was no Correlation between BMI and Symptom Severity (using the total IPSS for Severity rating).

The average frequency of urination of this group at Baseline was 3.2 times per night. This reduced significantly, to 2.4 times at Month 1, 2.0 times at Month 2 and 1.3 times by Month 3.

The average Daytime Urinary Frequency was 8.7 times at Baseline (range of 3 - 18). There was a significant reduction in frequency after one (1 ) month of treatment, from 8.72 to 7.1 times per day (18.4% reduction). (This was significant at p<0.05). The trend continued after two (2) months of treatment with an average of 6.2 visits (or a 30% reduction in day time frequency. After 3 months of treatment, subjects recorded an average daily frequency of 5.6, (corresponding to a 35.6% reduction in frequency compared to baseline). Overall, there was a significant reduction in frequency. This value is comparable to urinary frequency in healthy people (Table 20).

Table 20: Avera e and % Reduction in Da time Urinar Fre uenc N= 33

Nocturia (Night Time Urinary Frequency)

The average Night Time Urinary Frequency was 3.3 times at baseline (range of 1 -9).

There was a significant reduction in nocturia after one (1) month of treatment (p<0.05) and this continued throughout the study. The frequency reduced to 2.4 times per night, (a 27% reduction, and range of 1 — 5 times per night). This result was similar to that recorded at two (2) months of treatment with an average of 2.0 visits (or a 29% reduction in nocturia, range being 1 - 4 times per night). There was further significant improvement after 3 months of treatment, with subjects recording an average nightly frequency of 1.3 times / night, (corresponding to a 61% reduction in nocturia compared to baseline, and a range of only 0-3 visits / night).

There were 5 subjects (50%) reporting a frequency of more than 3 times per night. The average frequency of this group at Baseline was 4.5 times per night. This reduced significantly, reduced to 2.8 times at Month 1 , 2.5 times at Month 2 and 1.5 times by Month 3 (Table 21 ).

Table 21: Average and % Reduction in Night time Urinary Frequency (Nocturia). N= 33

International Prostate Symptom Score (IPSS) Questions and ratings

2. ...had to urinate again less than two hours after you finished urinating?

3. ...stopped and started again several times when you urinated?

4. ...found it difficult to postpone urination?

5. ...had a weak urinary stream?

6. ...had to push or strain to begin urination?

The Maximum IPSS is 35 (maximum rating of all questions being 5). Ratings:

0 Not at all,

1 Less than 1 time in 5,

2 Less than half the time,

3 About half the time, 4 More than half the time,

5 Almost always

The IPSS uses the following rating system: 0 - 8 Mild Symptoms; 9 - 19 Moderate Symptoms; 20 - 35 Severe Symptoms.

IPSS Total - average, average % reduction

Subjects reporting a total IPSS of >9 (Moderate/Severe Symptoms) were eligible for study. This study involved 23 subjects with total IPSS symptom scores at baseline ranging from 11 - 33, with an average rating of 19.1.

Of these, 14 subjects had symptoms classified as having Moderate Symptoms (IPSS 9 - 19) and 9 subjects classified as having Severe Symptoms (IPSS 20 - 35).

The average total IPSS score at Baseline was 19.1. This reduced slightly after one (1) month of treatment to 15.8, corresponding to a 17.3% reduction in IPSS. After two (2) months of treatment, the average IPSS further reduced to 13.9, corresponding to a 27.2% reduction in IPSS. The overall IPSS results recorded after three (3) months of treatment was 12.2, which corresponded to a 36.1% reduction in IPSS. These changes at month 1, 2 and 3 were significant (p<0.05) (Table 22).

Table 22: Total IPPS Score: Average and % Reduction from Baseline in Symptoms.

After 3 months of treatment the subjects were reclassified according to the IPSS. Eight participants were now classified as mild, 11 as moderate and 3 as severe.

Urinary Flow

Questions 1 - 4 & 6 relate specifically to aspects of Urinary Flow. The results in this study show that 50% of subjects reported that these symptoms occurred at least 50% of the time. There was an average reduction of approximately 20% in IPSS for Q1-4, & Q6 at Month 1. After 2 months of treatment there was a greater improvement observed, with average reduction (compared to baseline) reported to be 29 - 36%. Further significant improvements were observed after month 3 (approximately 45 - 49% average reduction). Weak Urinary Stream

In this study, 30% of the group reported a rating of 5 (Almost Always) for Q5 at baseline. ( .. "weak urinary stream" ...). Another 43% gave a rating of 3-4 (from half to more than half the time. This shows that majority of men experience a weak urinary stream. There was a slight reduction (10%) after month 1 of treatment with no further improvement by Month 2 (11%) and an average reduction in symptoms of 15% by Month 3.

Urinary Distress Inventory

There was a significant improvement in Quality of Life, as assessed by UDI. There was a change from Mostly Dissatisfied to Equally Satisfied/Mostly Satisfied in the Quality of Life question. At completion of the study, 29 of the 33 subjects (88%) wanted to continue with treatment. The UDI is a standardized disease-specific questionnaire used to detect bothersome incontinence in older people. The question "How much are you bothered' by a symptom is assessing Quality Of Life.

This is different to the IPSS which asks for specific quantitative data {How often does this symptom occur).

Table 23: Urinary Distress Inventory

Do you experience, and if so, how much are you bothered by:

1. Frequent urination

2. Leakage due to feeling or urgency

3. Leakage due to activity, coughing, sneezing

4. Small amounts of leakage (drops)

5. Difficulty emptying bladder

6. Pain or discomfort in lower abdominal or genital area

Ratings: 0, No; 1 , slightly; 2, moderately; 3 greatly

The most highly scored symptom was Question 1 ( frequency ). This correlates well with the frequency diary and the IPSS₁ (that indicate that urinary frequency during the day and night is the most commonly observed and most distressing symptom). There was a general improvement, shown by a 32% reduction in average bothered scores (from Moderate/ Severely Bothered to Slightly Bothered).

The Q5 ( Difficulty emptying bladder ) was also identified as a distressing symptom affecting quality of life, with an average bothered score of 1.6. After month 3 of treatment, there was a significant reduction to 0.48 at Month 3 (representing a 70% reduction).

The subjects rated the other symptoms, (Q2, 3, 4, 6) as being less bothered by them (Score of 1 or less), although these symptoms also improved over the 3 months of the study. However, together the IPSS and UDI show a significant positive trend of reduction in symptoms and an increase in Quality of Life.

The Quality of Life was assessed using a single question. "If you were to spend the rest of your life with your urinary condition the way it is now, how would you feel about that?"

0. Delighted

1. Pleased

2. Mostly satisfied

3. Mixed - about equally satisfied and dissatisfied

4. Mostly dissatisfied

5. Unhappy

6. Terrible

The average rating prior to treatment was 3.95 (with a range of 2 - 5). This reduced slightly at month 1 (average 3.4, range of 1 - 5). This did not change significantly at Month 2 (average 3.2, range 0 - 5). However, at Month 3, subjects recorded an average of 2.9, range 0 - 5. Overall, this represents a change from Mostly Dissatisfied to Equally Satisfied/Mostly Satisfied at Month 3.

Conclusion

In conclusion, there was a significant reduction in symptoms by month 3 as a result of the Prostate Formulation. The effects on the bladder (frequency day and night) were the most positive and occurred within the first month. There were gradual improvements in symptoms of urinary flow and a change in the strength of the urinal stream.

EQUIVALENTS

While the invention has been described in connection with the specific embodiments thereof, it will be understood that it is capable of further modification. Furthermore, this application is intended to cover any variations, uses, or adaptations of the invention, including such departures from the present disclosure as come within known or customary practice in the art to which the invention pertains, and as fall within the scope of the appended claims.

Claims

CLAIMSWe claim:

1. A method of preventing or treating a disorder of the prostate, the method comprising administering to a subject afflicted with or at risk of the disorder of the prostate a herb- containing composition comprising: at least about 1 ,000 mg of Crateva nurvala stem/bark preparation and at least about 670 mg of a standardized Equisetum arvense stem extract, wherein the administration of the composition reduces the symptoms of the disorder of the prostate.

2. The method of claim 1, wherein the herb-containing composition is formulated in a dry delivery system.

3. The method of claim 1, wherein the herb-containing composition is formulated in a liquid delivery system.

4. The method of claim 1, wherein the herb-containing composition is formulated in a controlled-release vehicle.

5. The method of claim 1 , wherein the oral dosage unit is selected from the group consisting of: a tablet; dry powder; capsule; and caplet.

6. The method of any one of claims 1 -5, wherein the herb-containing composition further comprises at least one compound selected from the group consisting of:

(a) a Serenoa repens/serrυlata (Saw palmetto) berry preparation present at a concentration of at least about 107 mg of extract standardized to contain approx 85% fatty acids and sterols per oral dosage unit;

(b) a Pygeum africanυm bark preparation present at a concentration of at least about 100 mg dry weight, standardized to contain 2.5 mg phytosterols per oral dosage unit;

(c) an Urtica dioica (stinging nettles) root preparation present at a concentration of at least about 100 mg extract per oral dosage unit;

(d) a Lycopersicon escufentum (tomato) fruit concentration of at least about 333 mg, standardized to contain 0.1 mg of Lycopene, per oral dosage unit;

(e) a Curcubita pepo (pumpkin seed) seed preparation present at a concentration of at least about 10 g dry weight per oral dosage unit;

(f) a zinc concentration of at least about 3 mg dry weight equivalents per oral dosage unit; (g) a copper concentration of at least about 1 mg dry weight equivalents per oral dosage unit; (h) a selenium concentration of at least about 5 μg dry weight equivalents per oral dosage unit; (i) a cholecalciferol (Vitamin D3) concentration of at least about 200 IU dry weight equivalents per oral dosage unit; G) a vitamin E concentration of at least about 50 IU dry weight equivalents per oral dosage unit; (k) a vitamin B6 concentration of at least about 25 mg dry weight equivalents per oral dosage unit; (I) a vitamin C concentration of at least about 100 mg dry weight equivalents per oral dosage unit; (m) a glutamic acid (as l-glutamic acid) concentration of at least about 200 mg dry weight equivalents per oral dosage unit; (n) a glycine concentration of at least about 200 mg dry weight equivalents per oral dosage unit; and (o) an alanine concentration of at least about 200 mg dry weight equivalents per oral dosage unit.

7. The method of any one of claims 1-5, wherein the composition is co-administered with a second composition comprising at least one compound selected from the group consisting of:

(a) a Serenoa repens/serrulata (Saw palmetto) berry preparation present at a concentration of at least about 107 mg of extract standardized to contain approx 85% fatty acids and sterols per oral dosage unit;

(b) a Pygeum africanum bark preparation present at a concentration of at least about 100 mg dry weight, standardized to contain 2.5 mg phytosterols per oral dosage unit;

(d) a Lycopersicon esculentυm (tomato) fruit concentration of at least about 333 mg, standardized to contain 0.1 mg of Lycopene, per oral dosage unit;

(f) a zinc concentration of at least about 3 mg dry weight equivalents per oral dosage unit; (g) a copper concentration of at least about 1 mg dry weight equivalents per oral dosage unit; (h) a selenium concentration of at least about 5 μg dry weight equivalents per oral dosage unit; (i) a cholecalciferol (Vitamin D3) concentration of at least about 200 IU dry weight equivalents per oral dosage unit; (j) a vitamin E concentration of at least about 50 IU dry weight equivalents per oral dosage unit; (k) a vitamin B6 concentration of at least about 25 mg dry weight equivalents per oral dosage unit; (I) a vitamin C concentration of at least about 100 mg dry weight equivalents per oral dosage unit; (m) a glutamic acid (as l-glutamic acid) concentration of at least about 200 mg dry weight equivalents per oral dosage unit; (n) a glycine concentration of at least about 200 mg dry weight equivalents per oral dosage unit; and (o) an alanine concentration of at least about 200 mg dry weight equivalents per oral dosage unit.

8. The method of claim 7, wherein the composition is administered to the subject contemporaneously with the second composition.

9. The method of claim 7, wherein the composition is administered to the subject before the second composition is administered to the subject.

10. The method of claim 7, wherein the composition is administered to the subject after the second composition is administered to the subject.

11. A herb-containing composition, comprising:

(a) a Crateva nυrvala stem/bark preparation present at a concentration of at least about 1,000 mg dry weight equivalents per oral dosage unit;

(b) a standardized Equisetυm arvense stem extract preparation present at a concentration of at least about 1 ,500 mg dry weight equivalents per oral dosage unit;

(c) at least one compound selected from the group consisting of:

(i) a Serenoa repens/serrulata (Saw palmetto) berry preparation present at a concentration of at least about 107 mg of extract standardized to contain approx 85% fatty acids and sterols per oral dosage unit; (ii) a Pygeum africanum bark preparation present at a concentration of at least about 100 mg dry weight, standardized to contain 2.5 mg phytosterols per oral dosage unit; (iii) an Urtica dioica (stinging nettles) root preparation present at a concentration of at least about 100 mg extract per oral dosage unit; (iv) a Lycopersicon esculentυm (tomato) fruit concentration of at least about

333 mg, standardized to contain 0.1 mg of Lycopene, per oral dosage unit; (v) a Curcubita pepo (pumpkin seed) seed preparation present at a concentration of at least about 10 g dry weight per oral dosage unit; (vi) a zinc concentration of at least about 1 mg dry weight equivalents per oral dosage unit; (vii) a copper concentration of at least about 1 mg dry weight equivalents per oral dosage unit; (viii) a selenium concentration of at least about 5 μg dry weight equivalents per oral dosage unit; (ix) a cholecalciferol (Vitamin D3) concentration of at least about 200 IU dry weight equivalents per oral dosage unit; (x) a vitamin E concentration of at least about 50 IU dry weight equivalents per oral dosage unit; (xi) a vitamin B6 concentration of at least about 25 mg dry weight equivalents per oral dosage unit; (xii) a vitamin C concentration of at least about 100 mg dry weight equivalents per oral dosage unit; (xiii) a glutamic acid (as l-glutamic acid) concentration of at least about 200 mg dry weight equivalents per oral dosage unit; (xiv) a glycine concentration of at least about 200 mg dry weight equivalents per oral dosage unit; and (xv) an alanine concentration of at least about 200 mg dry weight equivalents per oral dosage unit.

12. A herb-containing composition, comprising:

(a) a Crateva nυrvala stem/bark preparation present at a concentration of 1.OOOmg dry weight equivalents per oral dosage unit;

(b) a standardized Equisetum arvense stem extract preparation present at a concentration of 670 mg dry weight equivalents per oral dosage unit; (c) a Serenoa repens/serrulata (Saw palmetto) berry preparation present at a concentration of 107 mg of extract per oral dosage unit;

(d) a Lycopersicon esculentum (tomato) fruit concentration of 2.92 g, standardized to contain 0.5 mg of Lycopene, per oral dosage unit;

(e) a zinc concentration of 5 mg dry weight equivalents per oral dosage unit; and

(f) a selenium concentration of 8 μg dry weight equivalents per oral dosage unit.