WO2007144778A2

WO2007144778A2 - Herbal compositions for the prevention or treatment of a urinary tract infection

Info

Publication number: WO2007144778A2
Application number: PCT/IB2007/002847
Authority: WO
Inventors: Tracey Anne Speipel
Original assignee: Biologic Health Solutions Pty Ltd.
Priority date: 2006-02-22
Filing date: 2007-02-21
Publication date: 2007-12-21
Also published as: WO2007144778A3

Abstract

The present invention relates to herbal compositions for the prevention or treatment of a urinary tract infection, e.g., urethritis, cystitis, urethrocystitis, ureteritis, pyelonephritis, pyelitis, and pyelocystitis. Specifically, the invention provides compounds that contain C. nurvala and E. arvense and methods of use thereof.

Description

HERBAL COMPOSITIONS FOR THE PREVENTION OR TREATMENT OF A URINARY TRACT INFECTION

FIELD OF THE INVENTION

The present invention relates to herbal compositions for the prevention or treatment of a urinary tract infection, such as urethritis, cystitis, urethrocystitis, ureteritis, pyelonephritis, pyelitis, interstitial cystitis, and pyelocystitis.

BACKGROUND OF THE INVENTION

Urinary tract infections (UTIs) are common infections that usually occurs when bacteria enter the opening of the urethra and multiply in the urinary tract. The urinary tract includes the kidneys, ureters, bladder, and urethra. Urinary tract infections usually develop first in the lower urinary tract (urethra, bladder) and, if not treated, progress to the upper urinary tract (ureters, kidneys). The most common type of UTI is bladder infection (cystitis), and UTIs may afflict more than one part of the urinary tract. For instance, an infection of both the bladder and urethra is called urethrocystitis; and an infection of both the bladder and renal kidney is called pyelocystitis. Approximately 8 to 10 million people in the United States develop a UTI each year. Women develop the condition much more often than men, for reasons that are not fully known, although the much shorter female urethra is suspected. Although relatively rare, UTIs may afflict boys and young men. Twenty percent of women in the United States develop a UTI and 20% of those have a recurrence. Urinary tract infections in children are more common in those under the age of 2. Escherichia coli (E. coli) causes about 80% of UTIs in adults. Other bacteria (including

Staphylococcus saprophytics, Chlamydia trachomatis, and Mycoplasma hominis may also cause a UTI. E. coli is normally present in the colon and may enter the urethral opening from the skin around the anus and genitals.

Poor physical hygiene, sexual intercourse and urinary catheterization can also cause a UTI. Other risk factors include the following: bladder outlet obstructions (e.g., kidney stones, BPH), conditions that cause incomplete bladder emptying (e.g., spinal cord injury), congenital (present at birth) abnormalities of the urinary tract, suppressed immune system, hormonal changes during pregnancy and being uncircumcised.

Symptoms of lower UTIs (e.g., cystitis, urethritis) in adults include the following: back pain, blood in the urine (hematuria), cloudy urine, inability to urinate despite the urge, fever, frequent need to urinate, general discomfort (malaise) and painful urination (dysuria). Symptoms that indicate upper UTIs (e.g., pyelonephritis, pyelitis, ureteritis) in adults include the following: chills, high fever, nausea, pain below the ribs and vomiting

UTIs are treated with antibacterial drugs. The type of drug used and the duration of treatment depend on the type of bacteria. Most UTIs are treated with trimethoprim- sulfamethoxazole, amoxicillin, or fluoroquinolones. The infection may improve within a couple of days, but 1 to 2 weeks of medication may be prescribed to prevent a kidney infection. UTIs that are caused by bacteria such as chlamydia trachomatis and mycoplasma hominis require a longer course of treatment with tetracycline trimethoprim-sulfamethoxazole, or doxycycline. Surgery may be required for infections complicated by bladder outlet obstructions (e.g., kidney stone, BPH) and other risk factors (e.g., spinal cord injury). Kidney infections may require hospitalization and as many as 6 weeks of antibiotic treatment to prevent serious kidney damage.

Over-the-counter pain relievers and a heating pad may be used to relieve discomfort caused by a UTI. Frequent UTIs (3 or more per year) may be treated with low-dose antibiotics for 6 months or longer or with a 1 to 2 day course when symptoms appear.

A key problem with antibiotic usage is the side effect of the development of antibiotic drug resistance and the fact that the antibiotics do not prevent recurrence of the infection. In addition, pharmaceutical drug and herbal options for cystitis and UTIs commonly do not completely resolve both acute and chronic symptoms of cystitis and UTIs nor have clear success in preventing their recurrence.

Natural therapies may be used to treat a UTI. Compounds that may alkalize the urine and soothe the urinary membranes include citrate and Althea officinalis (Marshmallow root). Antiseptic herbs include Goldenseal root, Uva Ursi, Galium aparine (Cleavers), Bυchu and Zβa mays (Cornsilk). Vitamin C and immune supporting herbs such as Echinacea and Astragalus may also be recommended. Cranberry or blueberry juice have antibiotic properties that interfere with the ability of bacteria to adhere to the bladder or urethral tissue. Occasionally, a herb at the prescribed dose causes stomach upset or headache.

There are currently no medications that specifically target UTIs without having side effects elsewhere in the body. Accordingly, there is a need for the identification of new herb-containing compositions for the prevention and treatment of UTIs and their associated symptoms.

BRIEF SUMMARY OF THE INVENTION

The present invention provides methods of preventing or treating a urinary tract infection (UTI). The urinary tract infections can be urethritis, cystitis, urethrocystitis, ureteritis, interstitial cystitis, pyelonephritis, pyelitis, and pyelocystitis. In one embodiment, the invention provides a method of administering to a subject at risk of a UTI a herb-containing composition comprising: a Crateva nurvala (C. nurvala) stem/bark preparation present at a concentration at least about 1 ,500 mg dry weight equivalents per oral dosage unit; an Equisetum arvense (E. arvense) herb preparation at a concentration of at least about 1 ,000 mg dry weight equivalents per oral dosage unit; and a magnesium concentration of at least about 6 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-rβlease 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 ,500 mg dry weight equivalents per oral dosage unit. That is, the starting material is 1 ,500 mg of C. nurvala dry stem/bark. This starting material is eventually concentrated during the manufacture process to a ratio of 10:1 which equates to 150 mg of C. nurvala preparation. Accordingly, 150 mg of C. nurvala stem/bark preparation (which is concentrated) is equivalent to 1 ,500 mg dry weight of C. nurvala stem/bark or 1 ,500 mg of C. nurvala dry stem/bark starting material. The E. arvense herb preparation is present at a concentration of at least about 1 ,000 mg dry weight equivalents per oral dosage unit. That is, the starting material is 1 ,000 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 250 mg or 200 mg of E. arvense herb preparation. So, for example, 200 mg of E. arvense herb preparation (which is concentrated) is equivalent to 1,000 mg dry weight of E. arvense herb or 1 ,000 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. nurvala 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 ,000 mg dry weight of E. arvense herb or 1,000 mg of E. arvense dry herb starting material, which produces 200 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. nurvala 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. nurvala stem/bark preparation is present in the herb- containing composition at a concentration from about 500 mg to about 2,500 mg dry weight equivalents per oral dosage unit. In one embodiment, the C. nurvala stem/bark preparation is present in the herb-containing composition at a concentration from about 1 ,000 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 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 500 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 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 900 mg to about 1.100 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 10 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 15 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 28 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 another embodiment, the invention provides a herb-containing composition, comprising a C. nυrvala stem/bark preparation and a standardized E. arvense herb preparation with 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 iεoquercetrin and wherein the herb-containing composition is formulated as an oral dosage unit. 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 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 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 another aspect of the invention, the herb-containing composition further comprises or is co-administered with at least one of: (a) a Vacciniυm macrocarpon (Cranberry) fruit preparation present at a concentration of at least about 8,500 mg dry weight equivalents per oral dosage unit; (b) a Zea mays (Corn silk} preparation present at a concentration of at least about 2,000 mg dry weight equivalents per oral dosage unit; (c) an Achillea millefolium (Yarrow) preparation present at a concentration of at least about 3,000 mg dry weight equivalents per oral dosage unit; (d) an Althea officinalis (Marshmallow) root preparation present at a concentration of at least about 1,000 mg dry weight equivalents per oral dosage unit; (e) an Arctostaphylos uva-ursi (Bearberry) leaves preparation present at a concentration of at least about 1 ,400 mg dry weight equivalents standardized to contain 140 mg arbutin per oral dosage unit; (f) a Galium sparine (Cleavers) preparation present at a concentration of at least about 2,000 mg dry weight equivalents per oral dosage unit; (g) an Agathosma betυlina (Buchu) leaf preparation present at a concentration of at least about 1,500 mg dry weight equivalents per oral dosage unit; (h) an Echinacea angustifolia preparation present at a concentration of at least about 1,500 mg dry weight equivalents per oral dosage unit; (i) an Astragalus preparation present at a concentration of at least about 5 g dry weight equivalents per oral dosage unit; (j) a Vacciunium myrtillυs (Blueberry) fruit preparation present at a concentration of at least about 10 mg dry weight equivalents per oral dosage unit;

(k) a citrate preparation present at a concentration of at least about 100 mg dry weight equivalents per oral dosage unit; (I) a Vitamin C concentration of at least about 50 mg dry weight equivalents per oral dosage unit; (m) a Vitamin A concentration of at least about 1000 IU dry weight equivalents per oral dosage unit; and (n) a quercetin concentration of at least about 100 mg dry weight equivalents per oral dosage unit.

In another aspect, the invention provides methods of preventing or treating a UTI in a subject, by administering to the subject an herb-containing composition of the invention in an amount sufficient to prevent or treat the UTI.

In one embodiment, the invention provides a pharmaceutical composition comprising at least one of the herb-containing compositions of the invention and a pharmaceutically-acceptable carrier.

In one aspect, the invention provides a method of preventing or treating a urinary tract infection, the method comprising administering to a subject afflicted with or at risk of the urinary tract infection a herb-containing composition comprising: at least about 1 ,500 mg Cratβva nurvala stem/bark preparation and at least about 1,000 mg an Equisetum arvense stem extract preparation, wherein administration of the composition reduces the symptoms of the urinary tract infection. In one embodiment of the method of preventing or treating a urinary tract infection, the herb-containing composition is formulated in a dry delivery system. In one embodiment of the method of preventing or treating a urinary tract infection, the herb-containing composition is formulated in a liquid delivery system. In one embodiment of the method of preventing or treating a urinary tract infection, the herb-containing composition is formulated in a controlled-release vehicle. In one embodiment of the method of preventing or treating a urinary tract infection, the oral dosage unit is selected from the group consisting of: a tablet; dry powder; capsule; and caplet. In some embodiments of the method of preventing or treating a urinary tract infection, the herb- containing composition further comprises at least one compound selected from the group consisting of: (a) a Vaccinium macrocarpon (Cranberry) fruit preparation present at a concentration of at least about 8,500 mg dry weight equivalents per oral dosage unit; (b) a Zea mays (Corn silk) preparation present at a concentration of at least about 2,000 mg dry weight equivalents per oral dosage unit; (c) an Achillea millefolium (Yarrow) preparation present at a concentration of at least about 3,000 mg dry weight equivalents per oral dosage unit; (d) an Althea officinalis (Marshmallow) root preparation present at a concentration of at least about 1 ,000 mg dry weight equivalents per oral dosage unit; (e) an Arctostaphylos uva-ursi (Bearberry) leaves preparation present at a concentration of at least about 1400 mg dry weight equivalents standardized to contain 140 mg arbutin per oral dosage unit; (f) a Galium aparine (Cleavers) preparation present at a concentration of at least about 2,000 mg dry weight equivalents per oral dosage unit; (g) an Agathosma betulina (Buchu) leaf preparation present at a concentration of at least about 1 ,500 mg dry weight equivalents per oral dosage unit; (h) a Echinacea angustifolia or pallida flower preparation present at a concentration of at least about 1500 mg dry weight equivalents per oral dosage unit; (i) an Astragalus preparation present at a concentration of at least about 5,000 mg dry weight equivalents per oral dosage unit; and (j) a Vacciunium myrtillus (Blueberry) fruit preparation present at a concentration of at least about 10 mg dry weight equivalents per oral dosage unit; (k) a citrate preparation present at a concentration of at least about 100 mg dry weight equivalents per oral dosage unit; (I) a Vitamin C concentration of at least about 50 mg dry weight equivalents per oral dosage unit; and (m) a Vitamin A concentration of at least about 1000 IU dry weight equivalents per oral dosage unit; and (n) a quercetin concentration of at least about 100 mg dry weight equivalents per oral dosage unit. In some embodiments of the method of preventing or treating a urinary tract infection the composition is co-administered with a second composition comprising at least one compound selected from the group consisting of: (a) a Vaccinium macrocarpon (Cranberry) fruit preparation present at a concentration of at least about 8,500 mg dry weight equivalents per oral dosage unit; (b) a Zea mays (Corn silk) preparation present at a concentration of at least about 2,000 mg dry weight equivalents per oral dosage unit; (c) an Achillea millefolium (Yarrow) preparation present at a concentration of at least about 3,000 mg dry weight equivalents per oral dosage unit; (d) an Althea officinalis (Marshmallow) root preparation present at a concentration of at least about 1 ,000 mg dry weight equivalents per oral dosage unit; (e) an Arctostaphylos uva-ursi (Bearberry) leaves preparation present at a concentration of at least about 1400 mg dry weight equivalents standardized to contain 140 mg arbutin per oral dosage unit; (f a Galium aparine (Cleavers) preparation present at a concentration of at least about 2,000 mg dry weight equivalents per oral dosage unit; (g) an Agathosma betulina (Buchu) leaf preparation present at a concentration of at least about 1 ,500 mg dry weight equivalents per oral dosage unit; (h) a Echinacea angustifolia or pallida flower preparation present at a concentration of at least about 1500 mg dry weight equivalents per oral dosage unit; (i) an Astragalus preparation present at a concentration of at least about 5,000 mg dry weight equivalents per oral dosage unit; and G) a Vacciunium myrtillus (Blueberry) fruit preparation present at a concentration of at least about 10 mg dry weight equivalents per oral dosage unit; (k) a citrate preparation present at a concentration of at least about 100 mg dry weight equivalents per oral dosage unit; (I) a Vitamin C concentration of at least about 50 mg dry weight equivalents per oral dosage unit; and (m) a Vitamin A concentration of at least about 1000 IU dry weight equivalents per oral dosage unit; and (n) a quercetin concentration of at least about 100 mg dry weight equivalents per oral dosage unit. In one embodiment of the method of preventing or treating a urinary tract infection, the composition is administered to the subject contemporaneously with the second composition. In one embodiment of the method of preventing or treating a urinary tract infection, the composition is administered to the subject before the second composition is administered to the subject. In one embodiment of the method of preventing or treating a urinary tract infection, the composition is administered to the subject after the second composition is administered to the subject.

In another aspect, the invention provides an herb-containing composition, comprising: (a) a Crateva nurvala stem/bark preparation present at a concentration at least about 1,500 mg dry weight equivalents per oral dosage unit; (b) a Equisetum arvense stem extract preparation present at a concentration of at least about 1 ,000 mg dry weight equivalents per oral dosage unit; (c) magnesium present at a concentration of at least about 6 mg dry weight equivalents per oral dosage unit; and (d) at least one compound selected from the group consisting of: (i) a Vaccinium macrocarpon (Cranberry) fruit preparation present at a concentration of at least about 8,500 mg dry weight equivalents per oral dosage unit; (ii) a Zβa mays (Corn silk) preparation present at a concentration of at least about 2.000 mg dry weight equivalents per oral dosage unit; (iii) an Achillea millefolium (Yarrow) preparation present at a concentration of at least about 3,000 mg dry weight equivalents per oral dosage unit; (iv) an Althea officinalis (Marsh mallow) root preparation present at a concentration of at least about 1 ,000 mg dry weight equivalents per oral dosage unit; (v) an Arctostaphylos uva-υrsi (Bearberry) leaves preparation present at a concentration of at least about 1400 mg dry weight equivalents standardized to contain 140 mg arbutin per oral dosage unit; (vi) a Galium apariπe (Cleavers) preparation present at a concentration of at least about 2,000 mg dry weight equivalents per oral dosage unit; (vii) an Agathosma betulina (Buchu) leaf preparation present at a concentration of at least about 1 ,500 mg dry weight equivalents per oral dosage unit; (viii) a Echinacea angustifolia or pallida flower preparation present at a concentration of at least about 1500 mg dry weight equivalents per oral dosage unit; (ix) an Astragalus preparation present at a concentration of at least about 5,000 mg dry weight equivalents per oral dosage unit; and (x) a Vacciunium myrtillus (Blueberry) fruit preparation present at a concentration of at least about 10 mg dry weight equivalents per oral dosage unit; (xi) a citrate preparation present at a concentration of at least about 100 mg dry weight equivalents per oral dosage unit; (xii) a Vitamin C concentration of at least about 50 mg dry weight equivalents per oral dosage unit; and (xiii) a Vitamin A concentration of at least about 1000 IU dry weight equivalents per oral dosage unit; and (xiv) a quercetin concentration of at least about 100 mg dry weight equivalents per oral dosage unit. In another embodiment, the invention provides, an herb-containing composition, comprising: (a) a Crateva nurvala stem/bark preparation present at a concentration at least about 1,500 mg dry weight equivalents per oral dosage unit; (b) a Equisetυm arvensβ stem extract preparation present at a concentration of at least about 1,000 mg dry weight equivalents per oral dosage unit; (c) magnesium present at a concentration of at least about 6 mg dry weight equivalents per oral dosage unit; (d) a Vaccinium macrocarpon (Cranberry) fruit preparation present at a concentration of at least about 8,500 mg dry weight equivalents per oral dosage unit; and (e) a Vitamin C concentration of at least about 82 mg 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 a UTI, for example, urethritis, cystitis, urethrocystitis, ureteritis, pyelonephritis, pyelitis, interstitial cystitis, and pyelocystitis. 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. Typically, an oral dose is taken two-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 1 st 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.

Eqυisetum 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 a UTI, for example, urethritis, cystitis, urethrocystitis, ureteritis, pyelonephritis, pyelitis, interstitial cystitis, and pyelocystitis. Specifically, the invention identifies compounds that contain C. nurvala and E. arvense that are useful in the prevention and treatment of a UTI. 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 stem/bark extract per oral dosage unit. In another embodiment, the herb-containing composition of the invention contains from about 1,000 mg to about 2,000 mg dry weight equivalents C. nurvala stem/bark extract per oral dosage unit. In another embodiment, the herb-containing composition of the invention contains from about 1 ,200 mg to about 1 ,800 mg dry weight equivalents C. nurvala stem/bark extract per oral dosage unit. A C. nurvala stem/bark extract is an extract prepared using both the stem parts and bark of the C. nurvala herb. To prepare the herb-containing composition of the invention, the bark and stems of C. πurvala 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 500 mg to about 2,000 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 800 mg to about 1 ,200 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 900 mg to about 1,100 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.k.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 anal/sis 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 50°C 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 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 50°C 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 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. nυrvala 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 0.1 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 1 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 4 mg dry weight equivalents of magnesium to about 8 mg dry weight equivalents of magnesium per oral dosage unit. In one embodiment, the invention provides a herb-containing composition comprising: a

Crateva nυrvala (C. nυrvala) stem/bark preparation present at a concentration at least about

1,500 mg dry weight equivalents per oral dosage unit; an Equisetum arvense (E. arvense) herb preparation at a concentration of at least about 1,000 mg dry weight equivalents per oral dosage unit; and a magnesium concentration of at least about 6 mg dry weight equivalents per oral dosage unit.

In one embodiment, the herb-containing composition further comprises a vitamin B6 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 the vitamin B6 concentration, 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 magnesium citrate concentration of at least about 500 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 the magnesium citrate concentration, 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 quercetin 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 the quercetin concentration, 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. arvβnse leaf; Orange oil; J. virginiaπa stem; Myrrh oil; Orange flower oil; C. sempervirens leaf; d-alpha-tocopheryl acetate; diazolidinylurea; and hyd roxybe nzoates.

In one embodiment, the invention provides a method a method of treating or preventing a UTI, wherein the oral dosage unit is administered to the subject in an amount sufficient to treat or prevent the UTI. 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 an Vaccinium macrocarpon (Cranberry) fruit preparation, wherein Vaccinium macrocarpoπ is present at a concentration of at least about 8,500 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 the Vaccinium macrocarpon 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 Zea mays (corn silk) preparation, wherein Zea mays is present at a concentration of at least about 2,000 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 the Zea mays 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 Achillea millefolium (Yarrow) preparation, wherein Achillea millefolium is present at a concentration of at least about 3,000 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 the Achillea millefolium 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 Althea officinalis (Marshmallow) root preparation, wherein Althea officinalis is present at a concentration of at least about 2,000 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 the Althea officinalis 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 Arctostaphylos uva-ursi (bearberry) preparation, wherein Arctostaphylos uva-υrsi is present at a concentration of at least about 1 ,400 mg dry weight equivalents standardized to contain 140 mg arbutin per oral dosage unit. In another embodiment, the herb-containing composition is co-administered to the subject with a second composition comprising the Arctostaphylos uva-ursi 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 Galium aparine (Cleavers) herb preparation, wherein Galium aparine is present at a concentration of at least about 2,000 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 the Galium aparine 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 Agathosma betulina (Buchu) leaf preparation, wherein Agathosma betulina (Buchu) is present at a concentration of at least about 1 ,500 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 the Agathosma betulina 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 Echinacea angustifolia preparation, wherein Echinacea angustifolia is present at a concentration of at least about 1 ,500 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 the Echinacea angustifolia 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 Astragalus preparation, wherein Astragalus is present at a concentration of at least about 5 g 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 the Astragalus 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 Vacciunium myrtillus (Blueberry) fruit preparation of at least about 10 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 the Vacciunium myrtillus 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 citrate 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 citrate, 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 at a concentration of at least about 50 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 the Vitamin C concentration, 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 A at a concentration of at least about 1000 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 the Vitamin A concentration, 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 quercetin 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 the quercetin concentration, which may be administered contemporaneously with, or before, or after the herb-containing composition is administered to the subject.

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 a UTl, for example, urethritis, cystitis, urethrocystitis, ureteritis, pyelonephritis, pyelitis, interstitial cystitis, and pyelocystitis. 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); Pβngelly A. The constituents of medicinal plants: an introduction to the chemistry and therapeutics of herbal medicine. Sunflower Herbal 2^nd Edition, Merriwa, NSW₁ Australia, 1996; Lakshmi V. ef a/., Planta Medica, 32: 214-216 (1977).

The herb-containing compositions of the present invention are useful in the prevention and treatment of a UTI. Crateva and Equisetum have been shown to alter urinary electrolytes in such a way so as to reduce lithogenic potentiality. Varalakshmi P ef a/., J. Ethnopharmacology, 28: 313- 321 (1990); Anand R. et ah, Indian J. Pharmacology, 27: 265-268 (1995); Grases F. et al., Int. Urol. Nephrol.. 26(5):507-511 (1994). Crateva has also been found to inhibit small intestinal Na-K- ATPase. Varalakshmi P. et al., J. Ethnopharmacology, 31: 67-73 (1991 ). These effects may be due primarily to the presence of the sterol lupeol. A number of studies have shown that lupeol has anti-oxaluric and anti-calcuric effects leading to increased spontaneous passing of stones and symptomatic relief. Varalakshmi P et al., J. Ethnopharmacology, 28: 313-321 (1990); Anand R. ef al., Indian J. Pharmacology, 27: 265-268 (1995); Malini M. M., et al., Jpn. J. Med. Sci. Biol., 48(5- 6):211-20 (1995); Lakshmi V. ef al., Planta Medica, 32: 214-216 (1977). 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).

It has been hypothesized that this passage of the stone may be produced via a tonic contractile action of the drug on the smooth muscle. Varalakshmi P ef al., J. Ethnopharmacology, 28: 313-321 (1990); Anaπd R. et al., Indian J. Pharmacology, 27: 265-268 (1995); Deshpande P.J. et al., Indian J. Med. Res., 76(Suppl):46-53 (1982). Equisetum may also assist with incontinence via a similar mechanism. Kaempferol, luteolin and isoquercetin, found in Equisetum are documented to inhibit xanthine oxidase and subsequent urate calculi formation. Nagao A. et al., Biosci. Biotechnol. Biochem., 63(10): 1787-90 (1999). These herbal drugs act to improve the tone of the bladder wall. In 1982, Deshpande et al. reported that Crateva has beneficial effects on neurogenic bladder and post-prostatectomic atony of the bladder. See, Deshpande PJ. et al., Indian J. Med. Res., 76(Suppl): 46-53 (1982).

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, UK₁ 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-spasmαdic, 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 UTI. 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. TΛe 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 ai, 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 mors 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. Vaccinium macrocarpon (Cranberry; Vacciπium oxycoccus) is useful in the treatment and prevention of UTIs. Cranberries are a good source of vitamin C, potassium, and many micronutrients. Cranberries are also a rich source of flavanoids and phenolic compounds such as anthocyanins and proanthocyanidins, all of which are potent anti-oxidant, cell protective, and anti- cancer constituents. Cranberries also contain a number of organic acids including benzoic acid, malic acid, quinic acid, and citric acid. Cranberries, taken as a juice, have bacteriostatic effects well known for their effectiveness at preventing and treating urinary tract infections (UTI). Cranberry juice alters the pH of the urine, making it more acidic which in part inhibits certain types of bacteria from proliferating. E. coli bacteria, the most common type of UTI, is inhibited by cranberry juice. Besides changing the urinary pH, cranberry juice inhibits the adherence of bacteria to bladder cells through pectin-mediated compounds found in the fruit. Cranberries also inhibit the growth of several types of yeast. Nutrients and Foods in Aids Edited by Ronald R. Watson: CRC Pressi 998; Cranberry: a role in health promotion, Jeongmin Lee and Ronald R. Watson pg. 217-222. Vacciυniυm myrtillus (Blueberry) contains similar constituents as cranberry, and might also prevent bacteria from attaching to the lining of the urinary bladder. See, Ofek I et al., AnU-Escherichia coli adhesin activity of cranberry and blueberry juices. New Engl J Med 324:1599 (1991).

Clinical trials have shown Vaccinium macrocarpon (Cranberry) useful in the prevention of UTIs. In a double-blind trial, elderly women who drank 10 ounces (300 ml) of cranberry juice per day had a decrease in the amount of bacteria in their urine. See, AVOID J et al., Reduction of bacteriuria and pyuria after ingestion of cranberry juice. JAMA 271 :751-54 (1994). In another study, elderly residents of a nursing home consumed either four ounces (120 ml) of cranberry juice or six capsules containing concentrated cranberry daily for 13 months. During that time, the number of UTIs decreased by 25%. Dignam R et al., The effect of cranberry juice on UTI rates in a long term care facility. J. Am. Geriatr. Soc. 45:S53 (1997). A small preliminary trial found that supplementation with encapsulated cranberry concentrate (400 mg twice per day for three months) significantly reduced the recurrence of UTIs in women (aged 18-45) with a history of recurrent infections. Walker EB ef at., Cranberry concentrate: UTI prophylaxis. J Family Pract 45:167-68 (1997). Zea mays (Corn silk) and Agathosma betulina (Buchu) have a history of use in traditional herbal medicine as a urinary tract disinfectant and diuretic Doan DD, Nguyen NH, Doan HK, et al. Studies on the individual and combined diuretic effects of four Vietnamese traditional herbal remedies (Zea mays, lmperata cylindrica, Plantago major and Orthosiphαn stamineus). J Ethnopharmacol. 36:225-31 (1992); Leung AY & Foster S. Encyclopedia of Common Natural Ingredients Used in Food, Drugs and Cosmetics. New York: John Wiley and Sons 104—05 (1996). Likewise, Galium aparine (Cleavers) is a "soothing, relaxing and diffusive diuretic," which "increases aqueous excretion, corrects inability to pass normal catabolic wastes and relieves irritation." HealthWorld Online Page. 14 June 1998-9. 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 modem 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.

Flavanoids are herbal constituents that have been found useful in treating and preventing UTIs. For instance, freshly squeezed cranberry juice contains the flavonoids, quercetin and myricetin. Herbs containing flavanoids include Vaccinium macrocarpon (Cranberry), Althβa officinalis (Marshmallow), and Astragalus. Nutrients and Foods in Aids Edited by Ronald R. Watson: CRC Press1998: Cranberry: a role in health promotion, Jeongmin Lee and Ronald R. Watson pg. 217-222; Chen H, Zuo Y & Deng Y, Separation and determination of flavonoids and other phenolic compounds in cranberry juice by high-performance liquid chromatography. J Chromatogr A. 913 (1-2): 387-95 (2001 ); Shu HY. Oriental Materia Medica: A Concise Guide. Palos Verdes, CA: Oriental Healing Arts Press, 521-23 (1986). Achillea millefolium (Yarrow) is a urinary antiseptic that is indicated in infections such as cystitis. Tewari JP er a/., Phytopharmacologic studies of Achillea millefolium. Linn, J Tradit Chin Med 3(3):217-8 (1983); Peng Y et al., 65 cases of urinary tract infection treated by total acid of Achilleaalpina. J Ethnopharmacol 22(1 ): 1-9 (1988); Ibragimov Dl & Kazanskaia GB, Antimicrobial action of cranberry bush, common yarrow and Achilleabiebersteinii, J Pharm Sci 58(8):938- 41(1969).

Arctostaphylos uva-ursi (Bearberry) is used in Europe and in traditional herbal medicine in North America as a treatment for UTI. European Scientific Cooperative for Phytotherapy. Proposal for European Monographs, Vol. 3. Bevrijdingslaan, Netherlands: ESCOP Secretariat, 1992. The active constituent in uva υrsi is arbutin. In the alkaline environment of the urine, arbutin is converted into another chemical, called hydroquinone, which kills bacteria. Blumenthal M₁ Busse WR₁ Goldberg A, et al. (eds). The Complete German Commission E Monographs: Therapeutic Guide to Herbal Medicines. Austin: American Botanical Council and Boston: Integrative Medicine Communications, 1998, 224-5.

Echinacea angustifolia or pallida flower is useful in prophylaxis and treatment of upper respiratory tract infections and may be extended to urinary tract infections. See, Mahady GB. Echinacea: recommendations for its use in prophylaxis and treatment of upper respiratory tract infections. Nutr Clin Care 4(4): 199-208 (2001); Percival SS. Use of echinacea in medicine. [Review]. Biochem Pharmacol. 60(2):155-158 (2000).

UTIs benefit from an alkaline pH (less acidic). The easiest way to alkalinize the urine is with citrates, for instance, potassium citrate and sodium citrate. Oxford Handbook of General Practice, 552-553 (2002).

Vitamins are useful in the treatment and prevention of UTIs. Vitamin C has been shown to inhibit the growth of E. coli, the most common bacterial cause of UTIs. See, Sirsi M. Antimicrobial action of vitamin C on M. tuberculosis and some other pathogenic organisms. Indian J Med Sci; 6:252-55 (1952). In addition, vitamin C supplementation may also alkalize the urine. Axelrod DR. Ascorbic acid and urinary pH. JAMA 254:1310—11 (1985). Vitamin A deficiency increases the risk of many infections. Although much of the promising research with vitamin A supplements and infections has focused on measles, vitamin A is also thought to be helpful in other infections. Hussey GD & Klein M₁ A randomized, controlled trial of vitamin A in children with severe measles. N Engl J Med 323:160-64 (1990). 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 earner. 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 εtearate 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, polyorthoesters, 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 virginiana (Virginia cedarwood) stem oil, Commiphora myrrha (Myrrh) oil, Citrus aurantium (Neroli or Orange flower) oil, and Cυpressus 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 (NQ) 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 HQ 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. arvense (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 ef a/., Med Anthropol. Q. 13(3):267-85 (1999): Association for Continence Advice, Aust. Continence J.; 6(2):15-23 (2000); Robinson er a/., 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. nυrvala 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 HQ 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. Ail 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. ef a/.. 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. πurvala 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 PJ. et a/., 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 a!.. Arch. Int. Pharmacodyn. Ther., 330(1 ):76-89 (1995); Tapp A.J.S. et a/., 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. arveπse 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 manufactuήng 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:

(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 (HQ) 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 UQ 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. 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 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 seventy 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 (/ 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 k a , flavonoids) including isoquercetπn, galuteohn, and equisetnn. Isoquercetrin (a.k.a, isoquercβtrin; Quercetin 3-O-β-D-glucopyraπosιde, 4H-1-Benzopyran-4-one, 2-(3,4-dihydroxy-phenyl)-3-(β-D-glucofuranosyloxy)-5,7-dιhydroxy-) 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. 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% 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 maltodextriπ.

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.

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 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 MQ 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 following:

Household chores

Physical recreation

Entertainment activities

Travel >30 min from home

Social activities

Emotional health

Feeling frustrated

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 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 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)₁ 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 (UQ) 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 OAB₁ 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 (SiIiCOn 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 Equisetum 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 to Assess Efficacy of a Herbal Preparation Containing Crateva and Horsetail in Reducing the Severity and Reoccurrence of Urinary Tract Infections and the Symptoms of Cystitis

GENERAL Studies were conducted to investigate the effectiveness of a herb-containing natural therapeutic preparation in relieving urinary tract infection {i.e., UTI control test preparation) for oral administration. The UTI control test preparation was a natural herb-containing preparation formulated as a capsule.

MATERIALS AND METHODS Test Preparation

The UTI 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 and the minerals, calcium, magnesium phosphate and silicon. For example, each capsule contained dry weight equivalents as follows: C. nurvala stem/bark extract (1 ,500 mg), E. arvense stem extract preparation (1 ,000 mg), and magnesium 6 mg.

Study Design

Human subjects, having had experienced at least one urinary tract infection in the previous 3 months, were recruited through newspaper advertisements. All human subjects met the following criteria:

(a) had not undergone recent surgery on urinary tract within the last 12 months,

(c) were not currently being treated for psychotic disturbances, (d) did not use any medicine for urinary tract infection 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 two capsules of the UTI control test preparation daily over a period of 12 weeks. Other examples of clinical trials may account for different UTIs, including urethritis, cystitis, urethrocystitis, ureteritis, pyelonephritis, pyelitis, interstitial cystitis, and pyelocystitis, by selecting subjects afflicted with only certain kinds of UTIs.

The efficacy of the treatment was assessed primarily by measuring the frequency of UTI's in the 3 months prior to treatment compared to the 3 months of using the treatment. Additional information on the duration and severity of the UTI's, when they occurred, was also documented. RESULTS AND DISCUSSION Demographics

The study included 9 women aged between 26 and 65. Results All subjects had experienced at least 1 urinary tract infection in the 3 months prior to commencement of study: (2), 1 episode: (3), 2 episodes: (4) 3 episodes. After 3 months of treatment, 1 of the 9 subjects experienced two episodes, 4 of the 9 subjects experienced a single episode, with the remaining 4 having had no UTI's at all. This represents a reduction in the average number of episodes of 69%. Conclusion

The positive improvement (as measured by the reduction) in UTI recurrence in human test subjects receiving the UTI test preparation when compared to the number of UTI occurrences in the subjects prior to treatment demonstrates that the UTI formulation is of benefit to prevent a UTI and the associated symptoms. Example 8 Clinical Trial to Assess Efficacy of a Herbal Preparation Containing Crateva and Horsetail with Other Compositions in Reducing the Severity and Reoccurrence of Urinary Tract Infections and the Symptoms of Cystitis

GENERAL Studies were conducted to investigate the effectiveness of an herb-containing natural therapeutic preparation in relieving urinary tract infection (i.e., UTI control test preparation) for oral administration. The UTI control test preparation is a natural herb-containing preparation formulated as a capsule.

MATERIALS AND METHODS Test Preparation

The UTI 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 and minerals. For example, each capsule contained dry weight equivalents as follows: C nurvala stem/bark extract (1,500 mg), E. arvense stem extract preparation (1,000 mg), and magnesium 6 mg.

Each UTI control test preparation capsule was administered in combination with at least one of the following compositions: (1) Vaccinium macrooarpon (Cranberry) 8,500 mg; (2) Zea mays (Corn silk) 2,000 mg; (3) Achillea millefolium (Yarrow) 3,000 mg; (4) Althea officinalis (Marshmallow) 1 ,000 mg; (5) Arctostaphylos υva-υrsi (Bearberry) 1 ,400 mg standardized to contain 140 mg arbutin; (6) Galium aparine (Cleavers) 2,000 mg; (7) Agathosma betulina (Bυchu) 1,500 mg; (8) Echinacea angυstifolia 1 ,500 mg; (9) Astragalus 5 g; (10) Vaccluniυm myrtillus (Blueberry) 10 mg; (11 ) citrate 100 mg; (12) Vitamin C 82 mg; (13) Vitamin A 1000 IU; and (14) quercetin 100 mg. For example, one or more of these compositions were contained within the UTI control test preparation tablet or were co-administered with the UTI control test preparation capsule. In the case of co-administration, one or more of these compositions were administered to the subject before or after the UTI control test preparation capsule was administered to the subject.

Study Design

Human subjects containing at least one urinary tract infection in the previous 3 months were recruited through newspaper advertisements. Participants were also required to meet the following:

(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 currently enrolled in another investigational study

(d) no bladder biopsy / cystoscopy + biopsy (<30 days)

(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 human test subjects ingesting two capsules of the UTI control test preparation daily over a period of 12 weeks. Other examples of clinical trials may account for different UTIs, including urethritis, cystitis, urethrocystitis, ureteritis, pyelonephritis, pyelitis, interstitial cystitis, and pyelocystitis, by selecting subjects afflicted with only certain kinds of UTIs. The efficacy of the treatment was assessed primarily by measuring the frequency of UTI 's in the 3 months prior to treatment compared to the 3 months of using the treatment.

RESULTS AND DISCUSSION Demographics

The study included 8 women aged between 25 and 62, with an average age of 42 years. Results

All subjects had experienced at least 1 urinary tract infection in the 3 months prior to commencement of study: (2), 1 episode: (4), 2 episodes: 1; (4) episodes (almost consistently). After 3 months of treatment, 3 of the 8 subjects experienced a single episode, with the remaining 5 having no recurrence of UTI. This represents a reduction in the number of episodes from 2 to 0.4, an 80% reduction. Conclusion

The positive improvement as measured by the reduction in UTI reoccurrence in human test subjects receiving the UTI test preparation when compared to the same parameter in human test subjects prior to receiving the UTI control test preparation demonstrates that the UTI control test preparation is useful to prevent or treat a UTI in a human subject, e.g., urethritis, cystitis, urethrocystitis, ureteritis, pyelonephritis, pyelitis, interstitial cystitis, and pyelocystitis.

Example 9 Clinical Trial to Assess Efficacy of a Herbal Preparation Containing Crateva, Horsetail, and Cranberry in Reducing the Severity and Recurrence of Urinary Tract Infections and the Symptoms of Cystitis GENERAL

The study was conducted to investigate the effectiveness of a herb-containing therapeutic preparation (hereinafter called, UTI preparation or UTI test preparation) in treating the urologic symptoms associated with Urinary Tract Infection (UTI) and Cystitis in women aged between 20 and 70 years. The study assessed the efficacy of UTI preparation in preventing any further reoccurrences of UTI / cystitis in the following 6 month period while on the UTI test preparation.

The UTI test preparation was a natural herb-containing preparation formulated as a capsule. Each capsule contained extracts equivalent dry: Crateva nurvala stem/bark extract 1.5 g, Equisetum arvense (Horsetail) herb, 1.0 g, Vaccinium macrocarpon (Cranberry) fruit 8.5 g and Magnesium ascorbate, 100 mg.

MATERIALS AND METHODS Study Design

Women (aged between 20 and 70 years) experiencing recurrent cystitis were recruited through newspaper advertisements in Brisbane, Australia. Participants needed to have a history of UTI / cystitis that had been medically diagnosed and confirmed with urine cultures. A frequency of UTI / cystitis episodes of at least 3 times in the past 12 months was required. Participants were also required to meet the following:

(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)

(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 two times daily (equivalent to 3.0 g C. nurvala, 2.0 g E. arvense, 17.0 g V. macrocarpon and 200 mg magnesium ascorbate daily over a period of 6 to 12 months.

Women acted as their own controls. A detailed urogenital history including type, duration and severity of previous infections was taken prior to treatment. Participants took the treatment for a period of 6 to 12 months to monitor the number of reoccurring episodes that occurred during this time.

The results of these questionnaires were analyzed using the paired t-test. Test Preparation The UTI 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, V. macrocarpon, and Magnesium ascorbate. The study was conducted according to the TGA¹S "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

The study included 16 women aged between 20 and 66, with an average age of 42 years. Results

All subjects had experienced at least one urinary tract infection in the 3 months prior to ^■ commencement of study: (4), 1 episode (9), 2 episodes (1), 3 episodes, (2) 4 episodes (almost consistently). After 3 months of treatment, 8 of the 16 subjects (50%) did not experience any UTI's. Overall, there was an average reduction from 2.1 to 0.8 episodes of UTI's during the first 3 months of treatment.

After 6 months of treatment, 5 subjects still had not experienced a reoccurring UTI₁ although the remaining 3 subjects had experienced 1 UTI each. All, except one (1) subject, still experienced less UTI's from month 3 - 6 (in that 3 month period) than they did prior to commencement of treatment. One (1) subject was experiencing severe UTI's prior to and throughout the study. All medical and complementary interventions had been trialed but to date, none have been successful in helping this subject. Two (2) subjects took the UTI preparation for over 12 months and did not experience any recurring UTI Conclusion

Results from the trial indicate that the UTI preparation is effective in reducing the frequency of Cystitis infections over the 3 months and for some subjects may have a long term preventative role.

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 urinary tract infection, the method comprising administering to a subject afflicted with or at risk of the urinary tract infection a herb- containing composition comprising: at least about 1,500 mg Crateva nurvala stem/bark preparation and at least about 1 ,000 mg an Equisetum βrvense stem extract preparation, wherein administration of the composition reduces the symptoms of the urinary tract infection.

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 Vaccinium macrocarpon (Cranberry) fruit preparation present at a concentration of at least about 8,500 mg dry weight equivalents per oral dosage unit;

(b) a Zea mays (Corn silk) preparation present at a concentration of at least about 2.000 mg dry weight equivalents per oral dosage unit;

(c) an Achillea millefolium (Yarrow) preparation present at a concentration of at least about 3,000 mg dry weight equivalents per oral dosage unit;

(d) an Althea officinalis (Marshmallow) root preparation present at a concentration of at least about 1 ,000 mg dry weight equivalents per oral dosage unit;

(e) an Arctostaphylos uva-ursi (Bearberry) leaves preparation present at a concentration of at least about 1400 mg dry weight equivalents standardized to contain 140 mg arbutin per oral dosage unit;

(f) a Galium aparinβ (Cleavers) preparation present at a concentration of at least about 2,000 mg dry weight equivalents per oral dosage unit;

(g) an Agathosma betulina (Buchu) leaf preparation present at a concentration of at least about 1,500 mg dry weight equivalents per oral dosage unit; (h) a Echinacea angustifolia or pallida flower preparation present at a concentration of at least about 1500 mg dry weight equivalents per oral dosage unit; (i) an Astragalus preparation present at a concentration of at least about 5.000 mg dry weight equivalents per oral dosage unit; and G) a Vacciunium myrtillus (Blueberry) fruit preparation present at a concentration of at least about 10 mg dry weight equivalents peroral dosage unit; (k) a citrate preparation present at a concentration of at least about 100 mg dry weight equivalents peroral dosage unit; (I) a Vitamin C concentration of at least about 50 mg dry weight equivalents per oral dosage unit; and (m) a Vitamin A concentration of at least about 1000 IU dry weight equivalents per oral dosage unit; and (n) a quercetin concentration of at least about 100 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:

(b) a Zea mays (Corn silk) preparation present at a concentration of at least about 2,000 mg dry weight equivalents per oral dosage unit;

(e) an Arctostaphylos υva-υrsi (Bearberry) leaves preparation present at a concentration of at least about 1400 mg dry weight equivalents standardized to contain 140 mg arbutin per oral dosage unit;

(f) a Galium aparine (Cleavers) preparation present at a concentration of at least about 2,000 mg dry weight equivalents per oral dosage unit;

(g) an Agathosma betυlina (Buchu) leaf preparation present at a concentration of at least about 1,500 mg dry weight equivalents per oral dosage unit;

(h) a Echinacea angustifolia or pallida flower preparation present at a concentration of at least about 1500 mg dry weight equivalents per oral dosage unit;

(i) an Astragalus preparation present at a concentration of at least about 5,000 mg dry weight equivalents per oral dosage unit; and

(j) a Vacciunium myrtillus (Blueberry) fruit preparation present at a concentration of at least about 10 mg dry weight equivalents per oral dosage unit; (k) a citrate preparation present at a concentration of at least about 100 mg dry weight equivalents per oral dosage unit; (I) a Vitamin C concentration of at least about 50 mg dry weight equivalents per oral dosage unit; and (m) a Vitamin A concentration of at least about 1000 IU dry weight equivalents per oral dosage unit; and (n) a quercetin concentration of at least about 100 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. An herb-containing composition, comprising:

(a) a Crateva nurvala stem/bark preparation present at a concentration at least about 1 ,500 mg dry weight equivalents per oral dosage unit;

(b) a Equisetum arvense stem extract preparation present at a concentration of at least about 1,000 mg dry weight equivalents per oral dosage unit;

(c) magnesium present at a concentration of at least about 6 mg dry weight equivalents per oral dosage unit; and

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

(i) a Vacciniυm macrocarpon (Cranberry) fruit preparation present at a concentration of at least about 8,500 mg dry weight equivalents per oral dosage unit; (ii) a Zea mays (Com silk) preparation present at a concentration of at least about 2,000 mg dry weight equivalents per oral dosage unit, (iii) an Achillea millefolium (Yarrow) preparation present at a concentration of at least about 3,000 mg dry weight equivalents per oral dosage unit; (iv) an Althea officinalis (Marshmallow) root preparation present at a concentration of at least about 1 ,000 mg dry weight equivalents per oral dosage unit; (v) an Arctostaphylos uva-ursi (Bearberry) leaves preparation present at a concentration of at least about 1400 mg dry weight equivalents standardized to contain 140 mg arbutin per oral dosage unit; (vi) a Galium sparine (Cleavers) preparation present at a concentration of at least about 2,000 mg dry weight equivalents per oral dosage unit; (vii) an Agathosma betulina (Buchu) leaf preparation present at a concentration of at least about 1 ,500 mg dry weight equivalents per oral dosage unit; (viii) a Echinacea angustifolia or pallida flower preparation present at a concentration of at least about 1500 mg dry weight equivalents per oral dosage unit; (ix) an Astragalus preparation present at a concentration of at least about

5,000 mg dry weight equivalents per oral dosage unit; and (x) a Vacciunium myrtillus (Blueberry) fruit preparation present at a concentration of at least about 10 mg dry weight equivalents per oral dosage unit; (xi) a citrate preparation present at a concentration of at least about 100 mg dry weight equivalents per oral dosage unit; (xii) a Vitamin C concentration of at least about 50 mg dry weight equivalents per oral dosage unit; and (xiii) a Vitamin A concentration of at least about 1000 IU dry weight equivalents per oral dosage unit; and (xiv) a quercetin concentration of at least about 100 mg dry weight equivalents per oral dosage unit.

12. An herb-containing composition, comprising:

(a) a Crateva nυrvala stem/bark preparation present at a concentration at least about 1,500 mg dry weight equivalents per oral dosage unit;

(c) magnesium present at a concentration of at least about 6 mg dry weight equivalents per oral dosage unit;

(d) a Vaccinium macrocarpon (Cranberry) fruit preparation present at a concentration of at least about 8.500 mg dry weight equivalents per oral dosage unit: and

(e) a Vitamin C concentration of at least about 82 mg dry weight equivalents per oral dosage unit.