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WO2003011217A9 - Extraits de grifola et leurs procedes d'utilisation - Google Patents

Extraits de grifola et leurs procedes d'utilisation

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Publication number
WO2003011217A9
WO2003011217A9 PCT/US2002/023883 US0223883W WO03011217A9 WO 2003011217 A9 WO2003011217 A9 WO 2003011217A9 US 0223883 W US0223883 W US 0223883W WO 03011217 A9 WO03011217 A9 WO 03011217A9
Authority
WO
WIPO (PCT)
Prior art keywords
extract
grifola frondosa
component
composition
prostate
Prior art date
Application number
PCT/US2002/023883
Other languages
English (en)
Other versions
WO2003011217A3 (fr
WO2003011217A2 (fr
Inventor
Robert J Barry
Geetha Govindan
Andrew Miller
Original Assignee
Tanical Therapeutics Inc
Robert J Barry
Geetha Govindan
Andrew Miller
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Tanical Therapeutics Inc, Robert J Barry, Geetha Govindan, Andrew Miller filed Critical Tanical Therapeutics Inc
Priority to AU2002322702A priority Critical patent/AU2002322702A1/en
Publication of WO2003011217A2 publication Critical patent/WO2003011217A2/fr
Publication of WO2003011217A3 publication Critical patent/WO2003011217A3/fr
Publication of WO2003011217A9 publication Critical patent/WO2003011217A9/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/06—Fungi, e.g. yeasts
    • A61K36/07—Basidiomycota, e.g. Cryptococcus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to the treatment of disease using a phytochemical extract or fraction or component thereof. More specifically, the invention relates to the use of plant extracts and components of such extracts in the treatment of benign prostatic hyperplasia (BPH) and alopecia.
  • BPH benign prostatic hyperplasia
  • Benign prostatic hyperplasia (BPH, also known as benign prostatic hypertrophy), is a common nonmalignant enlargement of the prostate. Approximately 50% of all men older than 65 years have some degree of BPH and a third of these men have clinical symptoms consistent with bladder outlet obstruction (Hieble et al, 1986,
  • BPH is a heterogeneous disorder shown in studies to be caused by hormonal factors, growth factors, stromal-epithelial interactions, and aging. It is a progressive condition, typically manifest with a series of lower urinary tract symptoms (LUTS), including increased frequency of urination, nocturia, a weak urine stream, hesitancy or delay in starting the urine flow and incomplete bladder emptying.
  • LUTS lower urinary tract symptoms
  • the constellation of symptoms associated with intravesical obstruction is known as prostatism.
  • Chronic consequences of BPH can include hypertrophy of bladder smooth muscle, a decompensated bladder, an increased incidence of urinary tract infection, urinary stone formation and renal failure.
  • the static component is due to enlargement of the prostate gland, which may result in compression of the urethra and obstruction of the flow of urine from the bladder.
  • the dynamic component is due to increased smooth muscle tone of the bladder neck and the prostate itself (which interferes with emptying of the bladder) and is regulated by
  • alpha- 1 adrenergic receptors ⁇ l-ARs
  • the prostate is composed of fibromuscular tissue (30-
  • glandular epithelial cells 50-70%.
  • the fibromuscular component is present mostly anteriorly, while the glandular element is mostly in the posterior and lateral aspects of the organ.
  • the ratio of epithelium to smooth muscle in the prostate can vary substantially among individual men, from 1 :3 to 4: 1.
  • BPH prostate glands
  • larger prostate glands contain more androgen-dependent epithelial elements than smaller glands, which contain a higher proportion of smooth muscle, either case, the outcome of BPH may be urethral obstruction, induced dynamically by smooth muscle contraction and mechanically by epithelial overgrowth, or by a combination of both.
  • the medical treatments available for BPH address the dynamic and static components to varying degrees, and the therapeutic choices are expanding.
  • Surgical treatment options address the static component of BPH and include transurethral resection of the prostate (TURP), transurethral incision of the prostate (TUIP), open prostatectomy, balloon dilatation, hyperthermia, stents and laser ablation.
  • TURP is the preferred treatment for patients with BPH and approximately 320,000 TURPs were performed in the United States in 1990 at an estimated cost of $2.2 billion (Weis et al, 1993, Prostate 22:325-334).
  • surgery is an effective treatment for most men with symptomatic BPH, approximately 20-25% of patients do not have a satisfactory long-term outcome (Lepor et al, 1990, J. Urol 143: 533-537).
  • Complications include retrograde ejaculation (70-75% of patients), impotence (5-10%), postoperative urinary tract infection (5-10%), and some degree of urinary incontinence (24%) (Mebust et ⁇ /., 1989, J. Urol. 141:243-247). Furthermore, the rate of reoperation is approximately 15-20% in men evaluated for 10 years or longer (Wennberg et al, 1987, JAMA 257: 933-936).
  • DHT dihydrotestosterone
  • Finasteride (sold under the trademark PROSCA-R ⁇ ), for example, is a competitive and specific inhibitor of Type II 5- ⁇ -reductase, with which it slowly forms a stable enzyme complex. Finasteride has no affinity for the androgen receptor. (Gormley et al, 1992, N. Eng. J. Med. 327: 1185-1191). Lowering of DHT leads to shrinkage of the enlarged prostate gland in most men (17.9% reduction of total prostate volume) compared to subjects receiving placebo. This can lead to gradual improvement of symptoms and urine flow over the next several months.
  • Finasteride has also been shown to reduce the risk of acute urinary retention and the need for BPH-related surgery by 57% and 55%, respectively (McConnell et al, for the PROSCAET Long-Term Efficacy and Safety Study (PLESS) Group, 1998, NEngl JMed. 338:557-563). However, although finasteride is a potent 5- ⁇ -reductase inhibitor and
  • the balding scalp contains miniaturized hair follicles and increased amount of DHT, compared to the hairy scalp.
  • Administration of finasteride produces a reduction in serum and scalp DHT concentration, promoting hair growth. (Physicians' Desk Reference, 2001, 55th edition, page 2010).
  • the usefulness of finasteride is also limited due to a multitude of undesirable side effects including impotence, decreased libido, ejaculatory disorders, and breast enlargement and tenderness (Agency for Health Care Policy and Research (AHCPR), 1994, AHCPR Publication No. 940584).
  • finasteride causes a decrease in serum prostate specific antigen (PSA) levels by approximately 50% in patients with BPH, even in the presence of prostate cancer. This lowering of serum PSA levels may obscure its utility as a tumor marker for prostate cancer (1999, Facts and Comparisons, Finasteride monograph, St. Louis, Mo.: Facts and Comparisons, Inc.).
  • PSA prostate specific antigen
  • alpha-1 adrenergic receptor blocking agents which act by
  • ⁇ l-AR blockers e.g., terazosin (HYTRI-Sf, Abbott Laboratories), doxazosin
  • the ⁇ l-AR blockers provide prompt relief of symptoms, but do not
  • the ⁇ l-AR blocking agents have a more rapid onset of action (Steers et al, 1995, Dis.
  • U.S. Patent No. 5,854,404 to Nanba et al. discloses a method of isolating a high molecular weight glucan/protein complex from the maitake mushroom, Grifola. The complex had anti-tumor and immunopotentiating activity when administered to mice intraperitoneally.
  • Fullerton et al. 2000, Mol Urol. 4:7-
  • GR-tFRON ⁇ -D GD, Maitake Products, Inc., Ridgefield, NJ
  • Adenocarcinoma of the prostate presents histologically with large nucleoli, frequent mitoses, stromal invasion and involvement of perineural lymphatics.
  • Cancer cells are also genetically unstable and are known to be hypersensitive to therapeutic agents such as, for example, chemotherapeutic agents and radiation, thus forming the basis for many of the currently used approaches to treating cancerous tumors and other types of neoplastic tissues. Accordingly, treatment of prostatic cancer may involve total prostate resection, hormone control therapy, radiation, oral diethylstilbestrol and reduction of testosterone levels by orchiectomy or the administration of cyproterone, ketoconazole, LHRH, etc. These procedures are not typically used to treat BPH.
  • prostatic tissue of BPH patients is benign non-cancerous tissue.
  • prostatic tissue of BPH patients would not be expected to respond to therapeutic agents in the same manner as cancerous cells and tissue.
  • agents typically used to treat BPH e.g., finasteride or alpha- 1 antagonists, useful in treating prostatic cancer.
  • the invention provides phytochemical extracts and methods that are useful in the treatment of benign prostatic hyperplasia (BPH).
  • BPH benign prostatic hyperplasia
  • the invention provides a method of treating BPH by administering a composition comprising a pharmaceutically active extract of Grifola frondosa or component thereof to a patient in need of such treatment.
  • the invention provides a method of treating lower urinary tract symptoms (LUTS) associated with BPH comprising the step of administering a composition comprising a pharmacologically active extract of Grifola frondosa or a component thereof to a patient suffering from LUTS.
  • LUTS lower urinary tract symptoms
  • the invention provides methods of inhibiting the growth rate of prostatic tissue or otherwise reducing the rate of prostatic hypertrophy or hyperplasia in an individual suffering from BPH by administering a composition comprising a pharmacologically active extract of Grifola frondosa or component thereof to said individual.
  • a composition comprising a pharmacologically active extract of Grifola frondosa or component thereof to said individual.
  • the invention encompasses reducing the size the of the prostate in an individual suffering from BPH by administering a composition comprising a Grifola frondosa extract or component thereof.
  • the invention provides methods of preventing or reducing the risk of BPH in individuals by administering a composition comprising a pharmacologically active extract of Grifola frondosa or component thereof to said individual.
  • the invention comprises methods of treating BPH or LUTS associated with or due to BPH by administering a pharmacologically active extract of Grifola frondosa or component thereof in combination with an alpha-1 adrenergic antagonist compound.
  • the invention provides a method of treating alopecia (e.g., male pattern hair loss or androgenetic alopecia) by administering a composition comprising a pharmacologically active extract of Grifola frondosa or component thereof to a patient suffering from alopecia.
  • alopecia e.g., male pattern hair loss or androgenetic alopecia
  • the invention provides a method of promoting hair growth by administering a composition comprising a pharmacologically active extract of Grifola frondosa or component thereof to an individual suffering from hair loss, e.g., an individual suffering from alopecia, male pattern hair loss, or androgenetic alopecia.
  • the invention comprises pharmaceutical compositions comprising an extract of Grifola frondosa, preferably an aqueous extract of Grifola frondosa, or a component thereof.
  • the invention also comprises the use of these different extracts in the above-described methods.
  • the invention provides the use of an extract extract of
  • an alpha 1 -antagonist e.g., terazosin, doxazosin, prazosin or tamsulosin.
  • the invention provides the use of an extract extract of Grifola frondosa or a component thereof for the preparation of a medicament for inhibiting growth of prostatic tissue, inhibiting androgen or 5- ⁇ -reductase enzyme- dependent stimulation of prostatic tissue or promoting hair growth.
  • the invention provides the use of an extract extract of
  • Grifola frondosa or a component thereof for the preparation of a medicament for promoting hair growth or for the treatment of the conditions of alopecia, baldness, hair loss or thinning hair, either alone or in combination with a second agent effective in promoting hair growth or in treatment the aforementioned conditions, e.g., finasteride or minoxidil.
  • FIG. 1 Illustrates the anti-androgen effect of a Grifola frondosa extract on androgen dependent growth of prostatic tissue in histoculture.
  • Fig. 2 Illustrates the effect of a Grifola frondosa extract on 5- ⁇ -reductase-mediated androgen dependent growth of prostatic tissue in histoculture.
  • Fig. 3. Illustrates the average change in body weight of control animals and experimental animals treated with Grifola frondosa extracts (a) and (b).
  • Fig. 4. Illustrates the average change in prostate weight of control animals and experimental animals treated with Grifola frondosa extracts (a) and (b).
  • Fig. 5 Illustrates the inhibition of prostate growth in control animals and animals treated with Grifola frondosa extracts (a) and (b). DETAILED DESCRIPTION OF THE INVENTION
  • the invention provides methods of treatment for benign prostatic hyperplasia (BPH).
  • BPH benign prostatic hyperplasia
  • the methods involve administering a phytochemical extract to individuals suffering from BPH.
  • the phytochemical extract is from a member of the genus Grifola.
  • the phytochemical extract is from Grifola frondosa.
  • the extract may be prepared from any part of Grifola frondosa, such as, for example, the fruiting body or mycelia.
  • the extract is prepared from mycelia of Grifola frondosa.
  • the preferred embodiment of the invention is an extract of Grifola frondosa.
  • Exfracts according to the invention can be obtained by aqueous extraction of fresh or dried Grifola frondosa or parts thereof. Extraction may also be performed with a number of different organic solvents, including but not limited to water miscible solvents, and mixtures thereof with water.
  • the extraction can be performed hot or cold by the employment of any extraction technology, e.g., maceration, percolation or supercritical fluid extraction.
  • organic extraction solvents examples include acetone, methyl ethyl ketone, ethyl acetate and alkanols, preferably having 1 to 4 carbon atoms, and mixtures of all of the forgoing with water.
  • the preferred extraction temperature is close to the boiling point of the employed solvent due to extraction efficacy, but lower temperatures are also applicable making necessary a longer period of extraction.
  • the extraction can be made more selective for certain constituents of Grifola frondosa thus enhancing or reducing their content in the finished extract.
  • the content of phenolic glycosides can be increased by employing a more hydrophilic solvent while the content of lipidic or and other hydrophobic molecules in the finished product can be enhanced by employing a more lipophilic solvent.
  • a second step of processing such as liquid-liquid extraction or column chromatography, can be employed to remove or to concentrate and possibly isolate any constituent of the extract. Thereby any constituent of Grifola frondosa can be avoided or concentrated in a finished fraction.
  • Grifola frondosa can be standardized in the finished fraction for the purpose of manufacturing a pharmaceutical composition.
  • Grifola frondosa or parts thereof or an extract or component thereof can be combined with any other active ingredient or plant extract to potentiate the therapeutic action.
  • extract is a composition obtained from Grifola frondosa, as set forth above.
  • an “extract” comprises at least one compound effective in the treatment of, for example, BPH or alopecia.
  • the term “component” is a pharmaceutially active constituent of a Grifola frondosa extract or of a fraction of a Grifola frondosa extract.
  • pharmaceutically active extract or fraction or component thereof refers to an extract or fraction or component thereof comprising at least one compound that is effective in eliciting a biological, e.g., pharmacological effect, when administered to a subject, e.g., a patient.
  • Preferred subjects are mammals, e.g., humans.
  • a treatment for or “treating” BPH mean lessening or ameliorating at least one abnormal or undesirable condition associated with BPH.
  • treatment may be effected, for example, by reducing or ameliorating the effect of a physiological condition that leads to prostate hypertrophy.
  • Treatment may, for example, cause a reduction in the rate or amount of androgen-dependent growth of prostatic tissue.
  • Treatment also includes the inhibition, either direct or indirect, of 5- ⁇ -reductase activity in prostatic tissue.
  • Treatment also includes causing a reduction in the size of the prostate in an individual suffering from BPH or causing a reduction in the rate of prostate growth or hypertrophy.
  • treatment includes reducing or ameliorating the undesirable symptoms of BPH.
  • the foregoing are merely non-limiting examples of treatment of BPH. Other means and outcomes for treating BPH are also encompassed by the invention.
  • the invention provides methods for treatment of lower urinary tract symptoms (LUTS) associated with BPH, particularly those involving micturition (urination) disorder, such as dysuria, incontinence, and enuresis.
  • LUTS lower urinary tract symptoms
  • the methods involve administering to affected individuals a phytochemical extract for a sufficient time and in an amount effective for lessening or ameliorating at least one symptom of the micturition disorder.
  • symptoms include but are not limited to filling symptoms, urgency, incontinence and nocturia, as well as voiding problems such as weak stream, hesitance, intermittency, incomplete bladder emptying and abdominal straining.
  • a "patient”, “patient in need thereof, or patient or individual “suffering from” a condition refers to an invidividual with at least one clinical manifestation of said condition.
  • patients in need of treatment include individuals with hypertrophied prostatic tissues, whether symptomatic or asymptomatic.
  • Methods for determining size and other characteristics of the prostate, including prostatic hyperplasia, in otherwise asymptomatic individuals include, for example, trans-rectal digital examination and trans-rectal ultrasound. Cystoscopy also permits estimation of prostate gland size, but is not usually used unless symptoms are present.
  • patients in need of treatment for BPH or patients suffering from BPH are male individuals with manifest symptoms of BPH. Further preferred is where the symptoms are lower urinary tract symptoms (LUTS).
  • LUTS lower urinary tract symptoms
  • the American Urological Association has developed a questionnaire to quantitate the severity of symptoms in patients with BPH (Barry et al, 1992, J Urol. 148:1549-1557).
  • the AUA Symptom Index (AUASI) consists of seven questions related to the severity of urinary frequency, nocturia, weak urinary stream hesitancy intermittency, incomplete emptying, and urgency, each of which has a score of (0 to 5). The maximum score is therefore 35.
  • Patients with scores of (0 to 7) are considered to have mild prostatism and are good candidates for watchful waiting with periodic reevaluation.
  • Men with scores of (8 to 19) or (20 to 35) are considered to have moderate or severe prostatism, respectively, and usually require therapy to avoid complications.
  • An additional diagnostic measure that can provide objective information about a patient's ability to urinate is the urinary flow rate. It is an electronic recording of the velocity of the urine being expelled from the bladder during micturition and represents the single best noninvasive urodynamic test to assess bladder outlet obstruction. From several investigations, it has been learned that the peak value more specifically identifies men with BPH than does the mean rate. Also of importance is the fact that flow rate is dependent upon the patient's age and the volume of urine voided; with advancing age and decreasing urine volume, the flow rate diminishes. Nevertheless, for a man in the seventh and eighth decade of life who voids 150 ml or more, a peak urinary flow rate of 15 ml/second or greater should be interpreted as appropriate.
  • “Irritative symptoms” typically include frequency, urgency, nocturia and unstable bladder contractions. Efficacy of treatment may be determined by any method known in the art. Such methods include but are not limited determining voiding volumes, frequency of urination, and frequency and strength of bladder contractions in individuals with BPH or LUTS; or interviewing such individuals to determine if they have experienced the amelioration of any such symptom.
  • Other measures of efficacy include a measurable reduction, most preferably a clinically relevant reduction, of urine leakage related to feelings of urgency, urine leakage related to physical activity, coughing or sneezing, leakage of small amounts of urine (drops), difficulty in bladder emptying, general leakage not related to urgency or activity, nighttime urination, bedwetting, a feeling of incomplete bladder emptying, etc.
  • a measurable reduction most preferably a clinically relevant reduction, of urine leakage related to feelings of urgency, urine leakage related to physical activity, coughing or sneezing, leakage of small amounts of urine (drops), difficulty in bladder emptying, general leakage not related to urgency or activity, nighttime urination, bedwetting, a feeling of incomplete bladder emptying, etc.
  • the use of patient-questionnaires and scales to measure symptom severity is widely accepted (Barry et al, supra), complementing objective clinical measures and having the advantage of being inexpensive and potentially self- administered.
  • treatment of BPH comprises administering a combination of a phytochemical extract, preferably of Grifola frondosa, with at least one additional therapeutic agent, i.e., compound and/or composition.
  • the term “combination” is defined as administering two or more therapeutic agents as part of the same treatment regime.
  • therapeutic agents When administered in “combination”, therapeutic agents may be administered in single or separate dosage forms.
  • therapeutic agents of a combination When present in separate dosage forms, therapeutic agents of a combination may administered at the same time or at different times and in any order.
  • a phytochemical extract is administered in combination with an alpha- 1 adrenergic antagonist to treat BPH. More preferred is where the phytochemical extract treats the obstructive component of BPH and the alpha- 1 adrenergic antagonist treats the dynamic component of BPH.
  • a patient suffering from BPH is treated by a combination comprising a Grifola frondosa extract and an alpha- 1 antagonist selected from the group consisting of prazosin, terazosin, doxazosin and tamsulosin.
  • the alpha- 1 adrenergic antagonistic activity of the compounds useful in the invention renders them useful as agents acting on body tissues particularly rich in alpha-1 adrenergic receptors (such as prostate, urethra and bladder). Accordingly, the anti-adrenergic compounds within the invention, established as such on the basis of their receptor binding profile, can be useful, either alone or in combination with other agents, as therapeutic agents for the treatment, for example, of micturition problems associated with obstructive disorders of the lower urinary tract, including BPH.
  • baldness As used herein, the terms “baldness”, “hair loss” and “alopecia” are used to refer to the condition of loss of hair from the scalp, i.e., the balding of the scalp or a reduction of the number of hairs within a given area of the scalp (i.e., “thinning hair”). These conditions can be caused by or linked to, for example, the hereditary condition androgenetic alopecia.
  • treating or the “treatment of baldness, hair loss or alopecia or the term “promoting hair growth” comprises administering a pharmaceutical composition having the effect of increasing hair growth or the density of hair in a bald area of the scalp or an area of thinning hair, or decreasing the rate at which a bald area increases in size or decreasing the rate at which the number of hairs decreases in an area of thinning hair.
  • an exfract of Grifola frondosa or a component thereof is used to treat androgenetic alopecia.
  • a phytochemical extract of the invention or a component thereof can also be used in methods to treat baldness and promote hair growth by administration in combination with other agents that are known to be effective in the treatment of baldness and the promotion of hair growth.
  • agents include both 5- ⁇ -reductase
  • inhibitors e.g., finasteride
  • agents that are not known inhibitors of 5- ⁇ -reductase e.g., finasteride
  • a phytochemical extract of the invention or a component thereof is administered in combination with finasteride or minoxidil to treat baldness or promote hair growth in an individual suffering from baldness or thinning hair or in need of promotion of hair growth.
  • Therapeutic Applications encompasses pharmaceutical formulations comprising those listed above, as well as methods employing these formulations for treating BPH or dysfunction of the lower urinary tract such as dysuria, incontinence, and enuresis.
  • Dysuria includes urinary frequency, nocturia, urgency, and difficulty in emptying the bladder, i.e., a suboptimal volume of urine is expelled during micturition.
  • Incontinence syndromes include stress incontinence, urgency incontinence, and overflow incontinence.
  • Enuresis refers to the involuntary passage of urine at night or during sleep.
  • the invention also encompasses pharmaceutical formulations comprising those listed above, as well as methods employing these formulations for treating "baldness”, “hair loss” and “alopecia”.
  • an "effective amount" of the compound for treating a urinary disorder or alopecia is an amount that results in measurable amelioration of at least one symptom or parameter of the disorders described above.
  • the methods described herein are practiced by administering a pharmaceutically active Grifola frondosa extract or fraction or component thereof in an amount effective in the treatment of the aforementioned conditions.
  • An effective amount for treating the disorder can easily be determined by empirical methods known to those of ordinary skill in the art, such as by establishing a matrix of dosages and frequencies of administration and comparing a group of experimental units or subjects to each point in the matrix.
  • the exact amount to be administered to a patient will vary depending on the state and severity of the disorder and the physical condition of the patient.
  • a measurable amelioration of any symptom or parameter can be determined by an individual undergoing treatment, by a physician or other worker skilled in the art of healthcare, or be reported by the patient to the skilled worker. It will be understood that any clinically or statistically significant attenuation or amelioration of any symptom or parameter of BPH or urinary tract disorders or alopecia is within the scope of the invention.
  • Clinically significant attenuation or amelioration means perceptible to the patient and/or to the physician or other practitioner.
  • a single patient may suffer from several symptoms of dysuria simultaneously, such as, for example, urgency and frequency, either or both of which may be reduced using the methods of the present invention.
  • any reduction in the frequency or volume of unwanted passage of urine is considered a beneficial effect of the present methods of treatment and, thus, an amelioration of a symptom.
  • Grifola frondosa extract may typically be administered in a dosage of about 0.05-100 g per day. Typical dosages for preferred alpha-1 antagonists administered in combination with a Grifola frondosa extract may be found in the Physicians Desk Reference (PDR ⁇ , 2001, 55 th edition). Doxazosin may typically be administered at a dosage of about between 1- 8 mg per day; tamsulosin at a dosage of about 0.1-0.8 mg per day. Terazosin may typically be administered at a dosage of about 1-20 mg per day, more preferably at about 10-20 mg per day.
  • Prazosin may typically be administered at a dosage of about 1-40 mg per day, preferably at about 10-20 mg per day and still more preferably at about 15 mg per day. Efficacy of treatment will generally be determined after treatment has been carried out for a minimum of least about 6 weeks. More preferably, efficacy will be determined after treatment has been carried out for at least about 8 weeks. Most preferably, efficacy will be determined after treatment has been carried out for at least about 12 weeks.
  • compositions of the invention may be administered orally, parenterally, by spray inhalation, topically, rectally, nasally, buccally, or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, infra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the compositions are administered orally, intraperitoneally or intravenously. Most preferably, the compositions are administered orally.
  • Pharmaceutical compositions of the present invention may comprise a compound of the invention as an active ingredient or a pharmaceutically acceptable salt, thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients.
  • salts refers to salts prepared from pharmaceutically acceptable non-toxic inorganic or organic compounds including, including, for example bases, acids and tarfrates.
  • Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N- ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • basic ion exchange resins such as argin
  • compositions containing phytochemical extract or other active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non- toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and abso ⁇ tion in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the technique described in the U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for confrol release.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredients is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • an oil medium for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethycellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene- oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorb
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n- propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
  • preservatives for example ethyl, or n- propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n- propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n- propyl, p-hydroxybenzoate
  • flavoring agents such as sucrose, saccharin or aspartame.
  • sweetening agents such as sucrose, saccharin or aspartame.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerin, glycerin, glycerin, glycerin, glycerin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol
  • the pharmaceutical compositions of the invention may also be in the form of an oil-in- water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution, h addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be ⁇ employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of inj ectables .
  • compositions of the invention may also be administered in the form of a suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • creams, ointments, jellies, solutions or suspensions, etc., containing a compound of the invention are employed.
  • topical application shall include mouth washes and gargles.
  • Dosage levels of the order of from about 0.01 mg to about 140 mg kg of body weight per day are useful in the treatment of the above-indicated conditions, or alternatively about 0.5 mg to about 100 g per patient per day.
  • the above-indicated conditions may be effectively treated by the administration of from about 0.01 to about 500 mg of the compound per kilogram of body weight per day, or alternatively about 0.5 mg to about 100 g per patient per day.
  • the amount of active ingredient that may be combined with the carder materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • a formulation intended for the oral administration of humans may contain from 0.5 mg to 10 g of active agent compounded with an appropriate and convenient amount of carder material which may vary from about 5 to about 95 percent of the total composition.
  • Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient, for example 5 mg, 12.5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg or 500 mg.
  • the pharmaceutical formulations of the invention need not in themselves contain the entire amount of the agent that is effective in treating the disorder, as such effective amounts can be reached by administration of a plurality of doses of such pharmaceutical formulations.
  • Powdered Grifola frondosa mycelia (145 g) were mixed with boiling deionized water in two batches (total 1450 ml) for 10 min. While still hot, the mixture was then filtered through filter paper using a Buchner funnel. The filtrate was then lyophilized, yielding 32 g of pale yellow flakes that were labeled the "crude extract”.
  • a portion of the crude extract (820 mg) was suspended in 40 ml deionized water, heated to boiling and then centrifuged for 2 min at 2000 rpm at 18°C.
  • the supernatant (40 ml) was decanted and mixed with 13.3 ml of ethanol (25% EtOH final, v/v), leading to formation of a precipitate.
  • the mixture was allowed to stand overnight at 4°C.
  • the mixture was then centrifuged for 5 min at 2000 rpm to collect he precipitate.
  • the supernatant was decanted and the precipitate was dried in vacuo, yielding the "25% EtOH ppt.” (245 mg).
  • the supernatant (50.5 ml) was reduced in volume by evaporation 1 38 ml, followed by addition of ethanol (142 ml) to a final concentration of 80% (v/v). The mixture was held overnight at 4°C and then separated into precipitate and supernatant fractions by centrifugation. The supernatant fraction was decanted and the precipitate was dried, yielding the "80% EtOH ppt.” (352 mg). The supernatant was lyophilized, yielding the "final supernatant" fraction (668 mg). A "reconstituted extract” was obtained by combining dry aliquots of the 25% EtOH ppt., 80% EtOH ppt.
  • Crude extract 32 g material (dry weight) extract from 145 g starting material
  • composition of the invention on androgen-stimulated cell division within prostate tissue was determined by comparing [ 3 H] thymidine inco ⁇ oration in histoculture of rat prostate tissue treated with the Grifola frondosa crude extract and fractions and control agents.
  • Fresh prostate tissue was excised from adult male rats and put immediately into ice cold MEM medium and minced into cubes approximately lxlxl mm 3 in size. Minced tissue was then divided equally into 50-60 mg aliquots. Each aliquot was weighed and placed into a separate well of a 6-well culture dishes, completely immersed in MEM, and incubated at 37°C in 5% CO 2 atmosphere for 24 h. Following incubation, histocultures were provided with fresh medium and subjected to treatment with control or test agents.
  • Inhibition rates for each sample subjected to a test compound or positive-inhibition control were determined by measuring the cpm in each tissue sample treated with a test compound or 20 mM 4-HF, respectively, and dividing the measured value by the cpm of tissue samples that were maximally stimulated by addition of DHT.
  • DHT Dihydrotestosterone (20 nM)
  • HF 4-hydroxyflutamide (20 ⁇ M)
  • ventral prostate of anaesthetized adult male rat was dissected out from under the capsule and put immediately into cold MEM medium.
  • the tissue was then minced into small cubes using a surgical blade, divided into 100 mg aliquots and placed in a 6-well culture dish. Tissue was kept immersed in MEM medium. Treatment was begun immediately with the onset of histoculture. Each condition or treatment was performed in triplicate, i.e., on tissue samples contained in three separate wells.
  • tissue samples for inhibition of 5- ⁇ -reductase stimulation were treated with
  • [ 3 H]thymidine was added to each control or experimental sample and incubation was continued for an additional 24 h.
  • [ 3 H]Thymidine inco ⁇ oration was stopped by removing tissue samples from their respective wells and washing with ice-cold phosphate-buffered saline (PBS, pH 7.4). Tissue samples were then mixed with 4 ml scintillation liquid and radioactivity in each sample determined in a liquid scintillation counter.
  • Reconstituted extract 0.05 mg/ml + DHT 23 ⁇ 10 0.25 mg/ml + DHT 35 ⁇ 5
  • DHT Dihydrotestosterone (20 nM)
  • the average increase in body weight (bw) over the five weeks of the experiment for animals in the experimental and control groups (Groups II-NI) is given in Table 5 and shown in Fig. 3 a.
  • the average change in total prostate weight (pw) for each experimental or control group is given in Table 5 and shown in Fig. 4a. Values for average change in total prostate weight were determined by comparing the average of prostate weight determined at the end of treatment for animals in each of Groups II- VI to the average prostate weight of animals in Group I (0 time control).
  • the average inhibition of prostate growth is given in Table 5 and shown in Fig. 5 a. Values for inhibition of prostate growth were determined by comparing the average change in prostate weight for each freated group(Groups II-N) to the average change in prostate weight of the untreated control group(Group NI).
  • Group III Positive control of inhibition of prostate growth:
  • Body weights of animals in Goups II-V were determined every two weeks. At five weeks, experimental and control animals were weighed, sacrificed and their prostate glands were removed. Prostate glands were dissected, and weight was determined for total prostate, ventral prostate and dorsal prostate, for each animal.
  • the average increase in body weight (bw) over the five weeks of the experiment for animals in the experimental and confrol groups (Groups II-N) is given in Table 5 and shown in Fig. 3b.
  • the average change in total prostate weight (pw) for each experimental or control group is given in Table 5 and shown in Fig. 4b. Values for average change in total prostate weight were determined by comparing the average of prostate weight determined at the end of treatment for animals in each of Groups II-V to the average prostate weight of animals in Group I (0 time control).
  • the average inhibition of prostate growth is given in Table 5 and shown in Fig. 5b. Values for inhibition of prostate growth were determined by comparing the average change in prostate weight for each treated group(Groups II-IV) to the average change in prostate weight of the untreated control group(Group N).
  • a Grifola frondosa extract prepared as described in Example 1 is administered orally 1-3 times per day in doses of 0.05, 0.5, 5.0 and 10 g, for a period of 60 days. Daily dosages range from 0.05 to 30 g.
  • the therapeutic effect of treatment on prostate size is measured by determining prostate volume before and after treatment.
  • the therapeutic effect of treatment on LUTS measured by patient questionnaires, which are used to determine, e.g., urinary frequency, nocturia, urgency, difficulty with voiding, and pain or discomfort in lower abdominal or genital areas.
  • Effectiveness of the Grifola frondosa extract is measured in amelioration of any symptom associated with LUTS, as compared to a control patient group that is administered placebo, according to the same regimen.
  • Example 6 The treatment regimen of Example 6 is repeated with the exception that patients suffering from BPH are treated with a combination of a Grifola frondosa extract and an alpha- 1 antagonist.
  • Alpha- 1 antagonists are administered in doses of 0.02-10.0 mg one or two times daily.
  • Patients treated with the combination of the Grifola frondosa extract and alpha- 1 antagonist are compared to control groups of patients administered placebo, Grifola frondosa extract alone and alpha- 1 antagonist alone.

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Abstract

L'invention porte sur des extraits phytochimiques de la Grifola frondosa et en particulier sur des extraits aqueux et éthyliques. Lesdits extraits présentent in vitro une activité inhibitrice de la 5-α-réductase et des androgènes et s'avèrent de ce fait utiles pour traiter l'hyperplasie bénigne de la prostate et l'alopécie.
PCT/US2002/023883 2001-07-27 2002-07-29 Extraits de grifola et leurs procedes d'utilisation WO2003011217A2 (fr)

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