Use of (24S)-3b-hydroxy-5a-stigmastan-6-one in the treatment of prostatic hyperplasia, inflammation, or tissue fibrosis

Abstract

This disclosure generally relates to the use of (24S)-3β-hydroxy-5α-stigmastan-6-one in the preparation of a medicament for the treatment of benign prostatic hyperplasia, inflammation or fibrosis, and the medicament being administered to individuals in need of treatment at a dose of 0.1-50 mg / kg body weight.

Description

Technical Field

[0001] This invention relates to the application of a novel phytosterol in the field of biomedical technology, and particularly to the use of (24S)-3β-hydroxy-5α-stigmastan-6-one (PN06) in the treatment of benign prostatic hyperplasia, inflammation and tissue fibrosis. Prior Technology

[0002] Benign prostatic hyperplasia (BPH) is the most common benign tumor in older men, with an age-related incidence that accompanies the aging process. BPH is the most common cause of lower urinary tract symptoms (LUTS) in older men, such as increased urinary frequency and slow urine flow. For a long time, the most effective treatment was considered to be endoscopic prostatectomy via the urethra. However, this surgery also has known drawbacks, including bleeding and physiological stress, which can affect recovery in some patients. Furthermore, this surgery requires a high level of technical skill and typically necessitates a three- to five-day hospital stay. These factors have prompted the development of alternative therapies, including medication, minimally invasive surgical techniques, and other forms of endoscopic prostatectomy, aiming to achieve the same therapeutic effects as traditional surgery while reducing patient suffering and costs.

[0003] Furthermore, previously published literature indicates that acute and chronic inflammation is highly associated with LUTS and prostate hypertrophy, and is considered one of the causes of prostate fibrosis leading to bladder outlet obstruction. Inflammation can drive nociceptive signals as well as potential mechanisms for proliferative growth and tissue fibrosis.

[0004] Fibrosis is a pathological feature of most chronic inflammatory diseases. Fibrosis, also known as scarring, occurs when excessive extracellular matrix accumulates due to severe or repeated tissue damage. When fibrosis progresses significantly, it can eventually lead to organ dysfunction and even death. Fibrosis can affect almost every tissue in the body, including pulmonary fibrosis, cirrhosis, cardiac fibrosis, prostate fibrosis, and renal fibrosis. Although fibrosis is considered a major cause of high morbidity and mortality in most chronic inflammatory diseases, specific treatment strategies targeting the pathogenesis of fibrosis are currently extremely rare, if not nonexistent.

[0005] Lotus (Nelumbo nucifera Gaertn.), also known as water lily, belongs to the genus Nelumbo in the family Nelumbonaceae. It is a perennial aquatic plant widely distributed throughout Asia. Its green seed embryo, the lotus heart or lotus seed (Plumula nelumbinis, PN), has long been officially listed in several Chinese Pharmacopoes as a medicinal and food resource. On one hand, the lotus heart exhibits various pharmacological and clinical effects, such as antiarrhythmic, antihypertensive, anti-ischemic, diuretic, antipyretic, antiasthmatic, anti-restenosis, anti-neuropathic, antipsychotic, antidiabetic, anti-autoimmune, antiarrhythmic, anti-Alzheimer's, anticancer, hepatoprotective, anti-inflammatory, and anti-aging activities. However, since the presence of key compounds in PN with potential for treating benign prostatic hyperplasia and inhibiting tissue fibrosis has not yet been identified, the activities associated with these compounds remain to be verified.

[0006] In view of this, there is an urgent need in the field to identify active substances from PN that have the properties to treat benign prostatic hyperplasia, inflammation and tissue fibrosis. These active substances can serve as candidate compounds to develop treatments for diseases related to benign prostatic hyperplasia, inflammation and tissue fibrosis. Summary of the Invention

[0007] This summary is intended to provide a simplified overview of the present disclosure to enable the reader to gain a basic understanding of it. It is not a complete summary of the present disclosure and is not intended to identify key / critical elements of the embodiments of the invention or to define the scope of the invention.

[0008] One aspect of this invention relates to the use of (24S)-3β-hydroxy-5α-stigmastan-6-one (hereinafter referred to as PN06) in the preparation of a medicament, wherein the medicament is used to treat prostate enlargement, inflammation or tissue fibrosis in an individual, and the medicament is administered to the individual at a dose of 0.1-50 mg / kg body weight.

[0009] According to the embodiments disclosed herein, the drug can treat benign prostatic hyperplasia and is administered to the individual at a dose of 0.1-50 mg / kg body weight.

[0010] According to another embodiment of the present disclosure, the drug can inhibit LPS-induced inflammatory response in THP-1 monocytes, and its anti-inflammatory activity is superior to β-sitosterol, effectively reducing the pro-inflammatory cytokine IL-6.

[0011] According to another embodiment of this disclosure, the drug can inhibit tissue fibrosis. In one example, the drug can inhibit liver fibrosis; in another example, the drug can inhibit kidney fibrosis.

[0012] Preferably, the drug is administered to the individual at a dose of 3.5 mg / kg body weight, three times a week.

[0013] According to an optional embodiment of the present invention, the drug further comprises an anti-prostate hypertrophy drug. According to embodiments of the present disclosure, the drug for treating prostate hypertrophy can be a alpha-adrenergic blocker or a 5-alpha reductase inhibitor. Examples of alpha-adrenergic blockers suitable for use in the present invention include, but are not limited to, Terazosin, Doxazosin, Tamsulosin, Alfuzosin, Naftopidil, and Silodosin. Examples of 5-alpha reductase inhibitors suitable for use in the present invention include, but are not limited to, Finasteride and Dutasteride.

[0014] According to an optional embodiment of the present invention, the medicament further comprises an anti-inflammatory drug. According to embodiments of this disclosure, the anti-inflammatory drug may be a nonsteroidal anti-inflammatory drug (NSAID), a steroid drug, a conventional synthetic immunosuppressant, or a biologic. Examples of NSAIDs suitable for use in the present invention include, but are not limited to, ibuprofen, naproxen, meloxicam, diclofenac, and celecoxib. Examples of steroid drugs suitable for use in the present invention include, but are not limited to, prednisone, dexamethasone, hydrocortisone, and methylprednisolone. Examples of conventional synthetic immunosuppressants suitable for use in this invention include, but are not limited to, methotrexate, azathioprine, cyclophosphamide, cyclosporine, and azathioprine. Examples of biological agents suitable for use in this invention include, but are not limited to, anti-TNF-α drugs, anti-IL-6 receptor drugs, or anti-T-cell co-stimulation inhibitors. Examples of anti-TNF-α drugs suitable for use in this invention include, but are not limited to, etanercept, infliximab, adalimumab, or golimumab; examples of anti-IL-6 receptor drugs include, but are not limited to, tocilizumab; examples of anti-B-cell drugs include, but are not limited to, rituximab; and examples of anti-T-cell co-stimulation inhibitors include, but are not limited to, abatacept, etc.

[0015] According to an optional embodiment of the present invention, the medicament further comprises an anti-fibrotic drug. According to embodiments of this disclosure, the anti-fibrotic drug may be an anti-hepatic fibrotic drug or an anti-renal fibrotic drug. Examples of anti-hepatic fibrotic drugs suitable for use in the present invention include, but are not limited to, pirfenidone, nintedanib, adafermin, pegbelfermin, or saw palmetto; the anti-renal fibrotic drug is setanaxib and abatacept.

[0016] An individual suitable for treatment with the drugs disclosed herein is a mammal, for example, a human, mouse, rat, guinea pig, hamster, monkey, pig, dog, cat, horse, sheep, goat, dairy cow, and rabbit. Preferably, the individual is a human.

[0017] After reading the following embodiments, those skilled in the art will easily understand the basic spirit and other inventive objectives of the present invention, as well as the technical means and implementation methods adopted by the present invention. Simple Explanation of the Diagram

[0018] To make the above and other objects, features, advantages and embodiments of the present invention more apparent and understandable, the accompanying drawings are described below:

[0019] [No.] [1] [Illustrated] [PN06] [Effects on the reproductive system of aged mice] [ ](A) Representative appearance of the prostate, (B) Prostate weight quantification result, (C) Abdominal imaging, n=5 for each group, data are the mean ± standard deviation of five independent experiments.

[0020] [No.] [2] [Illustrated] [PN06] [or] [β-] [Sitosterol Pair] [LPS] [Induced human mononuclear cell line] [THP1] [The effect of the observed inflammatory activity] [ ] By inducing the production of the pro-inflammatory cytokine IL-6 in the human mononuclear cell line THP1 with lipopolysaccharide (LPS; 200 ng / mL), and simultaneously adding different concentrations of PN06 or β-sitosterol, the anti-inflammatory potential of PN06 compared with the phytosterol β-sitosterol was evaluated by enzyme-linked immunosorbent assay (ELISA) of IL-6.

[0021] [No.] [3] [Illustrated] [PN06] [right] [LPS] [Induced human mononuclear cell line] [THP1] [Effects of cytotoxicity testing and inflammatory activity] [ ](A) Cell viability, levels of pro-inflammatory cytokines (B) IL-1β, (C) IL-6, (D) TNF-α, and (E) TGF-β. Cell viability is expressed as a percentage relative to the control group, and data are the mean ± standard deviation of three independent experiments. Significant differences compared to the empty vector (DMSO) group are indicated by **p < 0.01, ***p < 0.001.

[0022] [No.] [4] [Illustrated] [PN06] [right] [LPS] [Induced] [RAW 264.7] [The Influence of Macrophage Inflammatory Activity] [ ](A)-(C) Contents of pro-inflammatory cytokines IL-1β, IL-6 and TNF-α, (D) Expression levels of COX2 and iNOS proteins in whole-cell lysates of RAW 264.7 cells, (E) is the result of quantitative analysis by immunospotting method of (D). Significant differences compared to the empty vector (DMSO) group are expressed as *p < 0.05, **p < 0.01, ***p < 0.001.

[0023] [No.] [5] [Illustrated] [PN06] [Effects on the physiological regulatory mechanisms of macrophages] [A] Protein expression levels of ERK, phosphorylated ERK (p-ERK), JNK, p-JNK, p38, and p-p38; (B–E) mRNA expression levels of IL-1β, IL-6, TNF-α, and TGF-β. Data are the mean ± standard deviation of three independent experiments. Significant differences compared to the empty vector (DMSO) group are expressed as *p < 0.05; **p < 0.01.

[0024] [No.] [6] [Illustrated] [PN06] [Effects on inflammatory activity and liver fibrosis] [A] Animal experimental design, (B) Mouse body weight curve, (C) - (D) Appearance of mouse liver tissue, (E) Results of Massen trichrome staining, (F) Expression levels of AST and ALT in mice. n=5 per group.

[0025] [No.] [7] [Illustrated] [PN06] [The impact of treatment on hepatocyte-related biological communication responses and gene expression] [A] RNA sequencing data analysis, (B) biological information point analysis, (C) AXL and GAS6 gene expression levels.

[0026] [No.] [8] [Illustrated] [PN06] [right] [HSC] [Activation and extracellular matrix] [(ECM)] [Impact of expression] [A] Expression levels of GAS6, AXL, phosphorylated PI3K (p-PI3K), PI3K, p-AKT, AKT, α-SMA, and COL1A1 proteins. (BC) are quantitative analyses of the immunoblotting results in (A). Significant differences compared to the empty vector group are expressed as follows: **p < 0.01, ***p < 0.001.

[0027] [No.] [9] [Illustrated] [PN06] [On human hepatic stellate cells] [HHSteC] [The Influence of Cell Cycle and Apoptosis] [A] Cell cycle distribution, (B) Proportion of apoptosis. The charts on the right are quantitative analyses of (A) and (B).

[0028] [No.]

[10] [Illustrated] [PN06] [right] [CCL4] [deal with] [HSC] [Activation and extracellular matrix] [(ECM)] [The impact of formation] [A] Expression levels of the marker proteins α-SMA and COL1A1, (B) Schematic diagram of the mechanism by which PN06 inhibits liver fibrosis.

[0029] As is customary practice, the various features and elements in the drawings are not drawn to scale. The drawing method is intended to best represent the specific features and elements related to the present invention. Furthermore, similar elements / components are referred to by the same or similar element symbols across different drawings. Implementation

[0030] To make the description of this disclosure more detailed and complete, illustrative descriptions of embodiments and specific examples of the present invention are provided below; however, these are not the only forms of implementing or utilizing the specific examples of the present invention. The embodiments cover features of multiple specific examples and methods and steps for constructing and operating these specific examples, as well as their order. However, other specific examples may also be used to achieve the same or equivalent functions and order of steps.

[0031] [I.] [definition] [ ]

[0032] For convenience, specific proper nouns used in this specification, embodiments, and appended claims are concentrated herein. Unless otherwise defined in this specification, the scientific and technical terms used herein have the same meaning as understood and commonly used by one of ordinary skill in the art to which this invention pertains. Furthermore, unless conflicting with the context, singular nouns used herein encompass their plural forms, and vice versa. Moreover, in this specification and the claims, expressions such as "at least one" and "one or more" have the same meaning, both representing a total of one, two, three, or more. Furthermore, in this specification and the claims, "at least one of A, B, and C," "at least one of A, B, or C," and "at least one of A, B, and / or C" refer to a total of only A, only B, only C, both A and B, both B and C, both A and C, and all three A, B, and C.

[0033] While the numerical ranges and parameters used to define the broader scope of this invention are approximate, the relevant values ​​in the specific embodiments have been presented as precisely as possible. However, any numerical value inevitably contains standard deviations due to individual testing methods. Here, "approximately" generally means that the actual value is within plus or minus 10%, 5%, 1%, or 0.5% of a specific value or range. Alternatively, the term "approximately" may mean that the actual value falls within the acceptable standard error of the average value, as determined by those skilled in the art to which this invention pertains. Except for experimental examples, or unless explicitly stated otherwise, it is understood that all ranges, quantities, values, and percentages used herein (e.g., to describe material usage, duration, temperature, operating conditions, quantity ratios, and the like) are modified with "approximately". Therefore, unless otherwise stated, the numerical parameters disclosed in this specification and the accompanying claims are approximate values ​​and are subject to change as needed. At a minimum, these numerical parameters should be understood as the indicated significant digits and values ​​obtained by applying general rounding. Here, a range of values ​​is expressed as a distance from one endpoint to another or between two endpoints; unless otherwise stated, the range of values ​​described herein includes the endpoints.

[0034] As used herein, the term "treatment" can refer to a curative or palliative measure. "Treatment" encompasses the partial or complete prevention, improvement, relief, and / or management of symptoms, secondary diseases, or conditions associated with benign prostatic hyperplasia (BPH), inflammation, or fibrosis. As used herein, "treatment" means the application or administration of the compounds or agents disclosed herein to an individual suffering from symptoms or diseases associated with BPH, inflammation, or fibrosis, or a secondary disease or condition secondary to BPH, inflammation, or fibrosis, with the aim of partially or completely alleviating, ameliorate, relieve, delay the onset, inhibit progression, reduce severity, and / or reduce the incidence of one or more symptoms, secondary diseases, or conditions associated with BPH, inflammation, or fibrosis. Symptoms, secondary diseases, and / or conditions associated with benign prostatic hyperplasia (BPH), inflammation, or fibrosis include, but are not limited to, fever, weakness, fatigue, weight loss, pain, cough, bleeding, skin changes, diarrhea or constipation, nausea, vomiting, and loss of appetite. Treatment may be given to individuals exhibiting early signs of these symptoms, diseases, and / or conditions to reduce the risk of developing symptoms, secondary diseases, and / or conditions associated with BPH, inflammation, or fibrosis. Treatment is generally considered "effective" if one or more symptoms or clinical manifestations or markers decrease, as defined herein. Alternatively, treatment is considered "effective" if the progression of symptoms, diseases, or conditions decreases or stops.

[0035] As used herein, the term "effective amount" refers to an amount of a component sufficient to produce the desired therapeutic effect. For therapeutic purposes, an effective amount can also refer to an amount in which any toxic or harmful effect of a component is outweighed by its beneficial therapeutic effect. The specific effective amount or sufficient amount can vary due to a variety of factors, such as the specific condition being treated, the patient's physical condition (e.g., weight, age, or sex), the species of mammal or animal being treated, the duration of treatment, the nature of any concurrent therapies, and the structure of the specific formulation and compound or its derivatives used. An effective amount can be expressed, for example, as the total mass of the active ingredient (e.g., in grams, milligrams, or micrograms), or as the ratio of the mass of the active ingredient to body weight (e.g., in milligrams per kilogram (mg / kg)). Alternatively, the effective amount can be expressed as the concentration of the active ingredient (e.g., drug PN06 as disclosed herein), such as molar concentration, mass concentration, volume concentration, molality, mole fraction, mass fraction, and mixing ratio. Specifically, the term "therapeuticly effective amount" in relation to the drug described herein refers to an amount of the drug sufficient to alleviate or improve symptoms associated with prostate enlargement, inflammation, or tissue fibrosis in an individual. Those skilled in the art can calculate the human equivalent dose (HED) of the drug (e.g., drug PN06 as disclosed herein) based on dosages determined in animal models. For example, the HED can be estimated as the maximum safe starting dose for human individuals according to the industry guidance issued by the U.S. Food and Drug Administration (FDA), "Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers."

[0036] As used herein, the terms "subject" or "patient" refer to an animal, including the human species, that can be treated with the compounds or agents described in this disclosure. Unless a sex is explicitly specified, the terms "subject" or "patient" refer to both males and females. Accordingly, the term "subject" or "patient" includes any mammal that may benefit from the administration of (24S)-3β-hydroxy-5α-stigmasterane-6-one (PN06). Illustrative "subjects" or "patients" include, but are not limited to, humans, rats, mice, guinea pigs, monkeys, pigs, goats, dairy cows, horses, dogs, cats, birds, and poultry. In one exemplary embodiment, the subject is a human.

[0037] [II.] [Detailed Description of the Invention]

[0038] This disclosure is based, in at least part, on the discovery that (24S)-3β-hydroxy-5α-stigmasterone-6-one (PN06) can treat prostate hypertrophy, suppress inflammation, and inhibit tissue fibrosis in an individual.

[0039] [1.] [This disclosure contains compounds]

[0040] Accordingly, this disclosure provides the use of (24S)-3β-hydroxy-5α-stigmastan-6-one ((24S)-3β-Hydroxy-5α-stigmastan-6-one) in the preparation of a medicament for treating prostate enlargement, inflammation, or tissue fibrosis in an individual. The (24S)-3β-hydroxy-5α-stigmastan-6-one (abbreviated as PNO6) has the following chemical structure (I): (I).

[0041] The PN06 compound disclosed herein can be obtained by extraction from natural herbs or through chemical synthesis. The natural herbs mentioned include, but are not limited to, those derived from, but are not limited to, white water lily (Nymphaea alba), fragrant water lily (Nymphaea odorata), red water lily (Nymphaea rubra), Eurasian water lily (Nuphar lutea), Japanese water lily (Nuphar japonica), lotus berthelotii (Lotus berthelotii), lotus corniculatus (Lotus corniculatus), Amazonian water lily (Victoria amazonica), Paraguayan water lily (Victoria cruziana), lotus (Nelumbo nucifera), yellow water lily (Nelumbo lutea), euryaleferox (Euryaleferox), white flower spike (Cabomba caroliniana), dwarf water lily (Brasenia schreberi), sympetalous lotus (Barclayalongifolia), Victoria water lily (Victoria regia), water lily (Nymphaea tetragona), ribbed water lily (Nuphar advena), small-leaved water lily (Nuphar microphylla), and snow-white water lily (Nymphaea). The lotus seeds of plants such as *Nymphaea candida*, *Nymphaea capensis*, *Nymphaea gigantea*, *Nymphaea lotus*, *Nymphaea micrantha*, *Nymphaea mexicana*, *Nymphaea minuta*, *Nymphaea nouchali*, *Nymphaea pubescens*, *Nymphaea stellata*, and *Nymphaea thermarum*.

[0042] Preferably, the PN06 compound disclosed herein can be extracted from the lotus seed core of *Nelumbo nucifera* using any extraction method well known in the art. Preferably, the PN06 compound disclosed herein can be obtained by mixing any of the aforementioned lotus seeds with an extractant (e.g., acetone, dichloromethane, ethanol (EtOH), ethyl acetate (EtOAc), n-hexane, water, etc.) for a sufficiently long time to prepare a crude extract.

[0043] Alternatively, the crude extract can be further purified to produce substantially pure PN06 compound. Generally, the crude extract can be purified by column chromatography (e.g., high-performance liquid chromatography, silica gel chromatography), thin-layer chromatography, recrystallization, or combinations thereof. In one operational example, the crude extract is subjected to silica gel chromatography to obtain substantially pure PN06 compound.

[0044] The purified compound is then identified by methods including, but not limited to, chemical analysis (e.g., titration, gravimetric analysis, or microspectroscopy), spectroscopic analysis (e.g., optical rotation spectroscopy, atomic spectroscopy, molecular spectroscopy, or infrared spectroscopy), mass spectrometry, nuclear magnetic resonance (NMR), proton spectroscopy, chromatographic analysis (e.g., column chromatography, ion exchange chromatography, gel chromatography, affinity chromatography, HPLC, or thin-layer chromatography), or combinations thereof (e.g., liquid chromatography-mass spectrometry (LC-MS)). In one operational embodiment, the PN06 compound is identified by NMR proton spectroscopy.

[0045] Depending on the purpose, the PN06 compound can be used as a pharmaceutical (including nutritional supplement) or a health food.

[0046] According to certain embodiments of this disclosure, the PN06 compound is used as a pharmaceutical product (or drug), in which case the pharmaceutical product may further comprise suitable carriers, excipients, and diluents commonly used in the manufacture of pharmaceutical products. Furthermore, the pharmaceutical product can be formulated into dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, sprays, topical preparations, suppositories, etc., for use as a sterile injection prepared according to conventional methods. Carriers, excipients, and diluents that may be included in the pharmaceutical product include lactose, dextran, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylparaben, propylparaben, talc, magnesium stearate, and mineral oil. In the case of formulations, excipients or diluents (e.g., fillers, expanders, binders, wetting agents, disintegrants, and surfactants) can be used for preparation. Oral solid dosage forms include tablets, pills, powders, granules, capsules, etc. These solid dosage forms include at least one excipient in the formulation, such as starch, calcium carbonate, sucrose, lactose, gelatin, etc. In addition, lubricants such as magnesium stearate or talc are used in addition to simple excipients. Oral liquid dosage forms include suspensions, solutions, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used as simple diluents, various excipients, such as wetting agents, sweeteners, flavoring agents, and preservatives, can be included in the formulation. Dosage forms for parenteral administration (injection) include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized formulations, and suppositories. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable esters (e.g., ethyl oleate). As a base for suppositories, mixed fatty acid glycerides (WITEPSOL), polyvinyl glycol (macrogol), polysorbate-61 (TWEEN-61), cocoa butter, lauryl oil, and glycerin gelatin may be used.

[0047] According to certain embodiments of this disclosure, when the PN06 compound is used as a health functional food, in addition to the active ingredient PN06, other ingredients commonly used in health functional foods may be added. For example, when it is made into a health functional beverage, citric acid, oligosaccharides, taurine, concentrated fruit juice, etc. may also be added.

[0048] 2. [This disclosure content] [PN06] [Uses of the compound]

[0049] According to the embodiments of the present invention, and the specific embodiments of the drug according to the disclosure, long-term supplementation with PNO6 can reduce age-related benign prostatic hyperplasia and maintain the integrity of abdominal organs in aged mice, inhibit lipopolysaccharide (LPS)-induced inflammatory response, and carbon tetrachloride (CCL4)-induced tissue fibrosis. Therefore, the PNO6 compound can be used to prepare a drug that can treat benign prostatic hyperplasia, inflammation and fibrosis.

[0050] According to the specific embodiments disclosed herein, the drug is administered to individuals in urgent need of treatment at a dose of approximately 0.01 to 1,000 mg / kg body weight, for example, at doses of 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, and 0.8 mg / kg body weight. 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93 Doses of 94, 95, 96, 97, 98, 99, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1,000 mg / kg body weight; preferably, a dose of about 0.1-100 mg / kg body weight is administered to the individual. According to certain embodiments of this disclosure, the disclosed drug is administered to the individual in need at a dose of about 0.1-50 mg / kg. In one operational embodiment, the disclosed drug is administered to the individual at a dose of about 3.5 mg / kg. This dose may be administered in a single aliquot or in more than one aliquot. Those skilled in the art or clinical practitioners may adjust the dosage or treatment regimen according to the patient's physical condition or the severity of age-related diseases or symptoms. According to certain embodiments of this disclosure, the drug is administered to the individual at least once a week, such as once, twice, three times, four times, or five times a week. Preferably, it is administered to the individual three times a week. According to other embodiments of this disclosure, the drug is administered to the individual at least once a day, such as once, two, three, or four times a day.

[0051] When it is understood that in the case of an individual suffering from a condition associated with benign prostatic hyperplasia, inflammation, or fibrosis, the uses of this disclosure may be administered to that individual alone, or in combination with an adjunctive therapy (e.g., surgery), or with an adjunctive medication that is beneficial in treating symptoms or conditions associated with benign prostatic hyperplasia, inflammation, or fibrosis. Depending on the intended therapeutic purpose, this disclosure may be administered to the individual before, during, or after the administration of the adjunctive therapy or medication.

[0052] In the treatment of benign prostatic hyperplasia (BPH), the additional medication further comprises an anti-BPH drug, wherein the anti-BPH drug may be a alpha-adrenergic blocker or a 5-alpha reductase inhibitor. Suitable alpha-adrenergic blockers for use in this invention include, but are not limited to, Terazosin, Doxazosin, Tamsulosin, Alfuzosin, Naftopidil, and Silodosin. Examples of suitable 5-alpha reductase inhibitors for use in this invention include, but are not limited to, Finasteride and Dutasteride.

[0053] In the treatment of inflammatory responses, the additional medication further comprises an anti-inflammatory drug, which may be a nonsteroidal anti-inflammatory drug (NSAID), a steroid, a conventional synthetic immunosuppressant, or a biologic. Examples of NSAIDs suitable for use in this invention include, but are not limited to, ibuprofen, naproxen, meloxicam, diclofenac, and celecoxib. Steroids suitable for use in this invention include, but are not limited to, prednisone, dexamethasone, hydrocortisone, and methylprednisolone. Examples of conventional synthetic immunosuppressants suitable for use in this invention include, but are not limited to, methotrexate, azathioprine, cyclophosphamide, cyclosporine, and azathioprine. Examples of biological agents suitable for use in this invention include, but are not limited to, anti-TNF-α drugs, anti-IL-6 receptor drugs, or anti-T-cell co-stimulation inhibitors. Examples of anti-TNF-α drugs suitable for use in this invention include, but are not limited to, etanercept, infliximab, adalimumab, or golimumab; examples of anti-IL-6 receptor drugs include, but are not limited to, tocilizumab; examples of anti-B-cell drugs include, but are not limited to, rituximab; and examples of anti-T-cell co-stimulation inhibitors include, but are not limited to, abatacept, etc.

[0054] In the treatment of tissue fibrosis, the additional medication further comprises an anti-tissue fibrosis drug, wherein the anti-tissue fibrosis drug may be an anti-hepatic fibrosis drug or an anti-renal fibrosis drug. Suitable anti-hepatic fibrosis drugs for use in this invention include, but are not limited to, pirfenidone, nintedanib, adafermin, pegbelfermin, or saw palmetto; the anti-renal fibrosis drugs are setanaxib and abatacept.

[0055] It should be noted that during the treatment period for which this disclosure is intended, different therapies or treatments may be administered to the individual via different routes, at different doses, at different time intervals, etc. Dosage and time intervals may vary due to factors as described above and depend on the professional considerations of the practitioner; and routes may include oral, enteral, oral, nasal, percutaneous, transmucosal, intravenous, intraperitoneal, intraarterial, intradermal, subcutaneous, and intramuscular routes.

[0056] Basically, the individual for whom the methods disclosed herein are applicable are mammals; preferably, the individual is a human.

[0057] The following examples illustrate certain aspects of the invention to facilitate implementation by those skilled in the art, and these examples should not be construed as limiting the scope of the invention. It is believed that those skilled in the art, upon reading the description herein, can fully utilize and practice the invention without excessive interpretation. All publicly available documents cited herein are considered an integral part of this specification.

[0058] [Example]

[0059] [Materials and Methods]

[0060] [1.] [Cell lines, antibodies] [siRNA] [、] [lncRNA] [Plasts and Drugs]

[0061] Normal human liver epithelial cell line THLE-3, human monocyte cell line THP-1, and mouse macrophage cell line RAW 264.7 were purchased from the American Type Culture Collection (ATCC) and cultured in DMEM medium containing 10% fetal bovine serum at 37˚C and 5% CO₂. Human liver stellate cell line (HHSteC, catalog number #5300) and stellate cell medium (catalog number #5301) were purchased from ScienCell Research Laboratories. Primary antibodies were purchased from Genetex (Irvine, California) and Cell Signaling Technology (Beverly Hills, Massachusetts), respectively. Secondary antibodies were purchased from Santa Cruz Biotechnology (Santa Cruz, California). PN06 powder (purity exceeding 98% as determined by high-performance liquid chromatography) was provided by Shanghai Baishi Biotechnology Co., Ltd. (Shanghai, China) and dissolved in DMSO to a final concentration of 100 mM.

[0062] [2.] [Quantitative instantaneous reverse transcription polymerase reaction] [(Quantitative real-time RT-PCR)]

[0063] Total ribonucleic acid (RNA) was isolated using the RNeasy mini kit (Qiagen), followed by quantitative real-time reverse transcription polymerase reaction (qRT-PCR) to detect the expression of GAS6, AXL, IL-1, IL-6, TNF-α, and TGF-β. The TaqMan gene expression analysis reagent (Thermo Fisher Scientific) was used; GAPDH was used as an internal control gene.

[0064] [3.] [Enzyme-linked immunosorbent assay] [(Enzyme-Linked Immunosorbent Assay, ELISA)]

[0065] The concentrations of interleukin-1β (IL-1β), interleukin-6 (IL-6), transforming growth factor-β (TGF-β), and tumor necrosis factor-α (TNF-α) in the culture medium were determined using an ELISA kit (Nanjing Jiancheng, Nanjing, China) according to the manufacturer's instructions.

[0066] [4.] [Massen's trichrome staining method] [(Masson's Trichrome Staining)]

[0067] First, 5-micron-thick paraffin-embedded tissue sections (FFPE) were dewaxed and hydrated with distilled water. Next, using Bouin's fixative as a mordant, the sections were treated at 56°C for 1 hour. After cooling, the sections were washed with tap water until the yellow color disappeared. The samples were then stained with Weigert's hematoxylin stain for 10 minutes, followed by thorough washing with tap water for 10 minutes, then stained with acid fuchsin solution for 15 minutes, and then washed with distilled water for 3 minutes. After washing, the slides were treated with phosphomolybdic acid solution for 10 minutes, followed by washing with distilled water for 10 minutes. Finally, they were stained with a light green solution for 2 minutes and washed with distilled water. After dehydration with alcohol, the slides were mounted with coverslips.

[0068] [5.] [Mouse]

[0069] Male BALB / c mice aged 6 to 8 weeks (purchased from the National Laboratory Animal Center, Taipei, Taiwan) were housed in a pathogen-free environment with a 12-hour light / 12-hour dark light cycle and fed autoclaved standard feed and drinking water. Mice were bred at the Animal Center of Chang Gung Memorial Hospital International Medical Center in accordance with the National Institutes of Health (NIH) Regulations Governing the Establishment and Management of Laboratory Animal Care and Use Committees or Subcommittees. All research related to animal experiments was reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) of Chang Gung Memorial Hospital International Medical Center.

[0070] [6.] Carbon tetrachloride [(CCL4)] [Induced mouse model of liver fibrosis]

[0071] The CCL4-induced liver fibrosis experiment in mice was conducted according to the experimental procedure of the mouse liver fibrosis model established in previously published literature (Fan, Xiaobao et al. “Attenuation of CCl4-induced hepatic fibrosis in mice by vaccinating against TGF-β1.”). Mice were intraperitoneally injected twice weekly with 2 µl / g CCL4 until death to induce liver fibrosis. The PN06 treatment group received intraperitoneal injections of 40 mg / kg PN06 three times weekly until death. Mice reached the experimental endpoint at 6 weeks of age and were sacrificed. Liver tissue was collected to observe liver fibrosis and inflammation. The control group received DMSO until death. Mouse body weight was measured weekly throughout the experiment, and weight changes were recorded.

[0072] [7.] [Immunohistochemistry]

[0073] Immunohistochemically stained slides were first incubated at 65°C for 30 minutes, then dewaxed with xylene and rehydrated with graded alcohols. They were then boiled in a microwave oven with Trilogy reagent (Cell Marque, Rocklin, CA) for 10 minutes to retrieval antigens. After washing, the slides were washed with 1x phosphate-buffered saline (PBS) and then immersed in 3% hydrogen peroxide solution for 10 minutes to inhibit endogenous peroxidase activity. After three washes with 1x PBS, the slides were incubated with primary antibody (Santa Cruz Biotechnology Inc., Santa Cruz, CA) at room temperature for 1 hour. After three more washes with 1x PBS, biotin-labeled secondary antibody (Dako, Glostrup, Denmark) was added and incubated for 25 minutes. After three more washes with 1x PBS, horseradish peroxidase-labeled streptavidin was added and incubated at room temperature for 25 minutes. Peroxidase activity was detected at room temperature using DAB substrate chromogen (Dako), and the slides were then counterstained with hematoxylin.

[0074] [8. THP-1] [Cell stimulation and cytokine analysis]

[0075] THP-1 mononuclear spheres (1 × 10⁶ cells per well) were seeded in 6-well culture dishes and induced to differentiate by treatment with 100 nM phorbol 12-myristate 13-acetate (PMA) for 24 hours. After differentiation, cells were pretreated with PN06 or β-sitosterol for 2 hours, followed by stimulation with lipopolysaccharide (LPS; final concentration 100 ng / mL) for 24 hours. The cell culture supernatant was collected by centrifugation (1,000 rpm, 4 °C, 5 min) for subsequent analysis. The concentrations of pro-inflammatory cytokines were quantified using an ELISA kit (BioLegend) according to the manufacturer's instructions.

[0076] [Example] [1] [Continuous updates] [PN06] [It can alleviate age-related prostate hypertrophy and maintain the integrity of abdominal organs in aged mice.]

[0077] In this embodiment, the effects of PN06 on the reproductive system of aged mice were assessed by measuring changes in the morphology and tissue weight of the testes and prostate in young mice (Y; 50 weeks), naturally aged mice (O; 130 weeks), and aged mice long-term supplemented with PN06 (O / PN06; 130 weeks). Aged mice long-term supplemented with PN06 (O / PN06; 130 weeks) were given the drug starting at 50 weeks of age by mixing PN06 into their diet and allowed free access to food. The prostate volume of aged mice (O) was significantly increased, exhibiting typical age-related prostate hypertrophy, while long-term PN06 treatment (O / PN06) effectively reduced prostate volume, with a morphology similar to that of the young group (Y) (Figure 1, (A)). Furthermore, prostate weight analysis showed a significant increase in prostate weight in the aged group (O), while long-term PN06 supplementation (O / PN06) significantly reduced prostate weight, indicating that PN06 can effectively inhibit age-related prostate hypertrophy (Figure 1, (B)). Observation of the abdominal visceral structure of mice showed that the aged group (O) had prostate hypertrophy and abnormal visceral tissue arrangement, while the PN06 group (O / PN06) exhibited a more compact and healthy visceral arrangement compared to the aged group (O), similar to that of young mice (Y) (Figure 1, (C)). In conclusion, PN06 can significantly inhibit age-related prostate hypertrophy and prevent the continued deterioration of the abdominal cavity in aged mice.

[0078] [Example] [2] [:] [PN06] [Compare] [β-] [Sitosterol inhibits more effectively] [THP-1] [In monocytes] [LPS] [Induced inflammatory response]

[0079] In this embodiment, to evaluate the anti-inflammatory potential of PN06 compared to the phytosterol β-sitosterol, THP-1 mononuclear globules were exposed to 200 ng / mL LPS, with or without a specified concentration of PN06 or β-sitosterol, and the concentration of the pro-inflammatory cytokine IL-6 was measured by ELISA. The results are shown in Figure 2.

[0080] As shown in the figure, compared with LPS-induced IL-6 secretion without PN06 or β-sitosterol, PN06 significantly inhibited LPS-induced IL-6 secretion in a dose-dependent manner, with 40 μM PN06 showing a significantly better inhibitory effect than 20 μM. Conversely, neither 20 μM nor 40 μM β-sitosterol could reduce IL-6 levels, and their effects were not significantly different from those of LPS alone. These results indicate that PN06 has superior anti-inflammatory activity compared to β-sitosterol and can effectively reduce the amount of IL-6 (Figure 2).

[0081] [Example] [3] [:] [PN06] [Can reduce inflammation]

[0082] [3.1] [Cytotoxicity] [ ]

[0083] In this embodiment, the human mononuclear cell line THP1 was used to evaluate the cytotoxicity of PN06 in normal cells. The survival rate of the aforementioned human normal cells was determined using MTT assay after 24 hours of treatment with increased PN06 concentration. The results showed that PN06 had no significant effect on cell survival rate below 40 μM; however, cell survival rate decreased slightly when the concentration exceeded 60 μM. Based on this, the present invention selected 10-40 μM as the applicable concentration range for subsequent experiments to ensure that it did not affect the survival rate of THP1 cells (Figure 3, (A)).

[0084] To determine the anti-inflammatory activity of PN06, this invention used the human mononuclear cell line THP1, pretreated with different concentrations of PN06 or empty vector (DMSO) for 2 hours, followed by the addition of 1 μg / mL LPS to induce an inflammatory response. After 24 hours of culture, the culture medium was collected, and cytokine concentrations were measured using ELISA. The results showed that PN06 significantly inhibited the secretion of pro-inflammatory cytokines IL-1β, IL-6, TNF-α, and TGF-β in THP1 cells, further confirming its anti-inflammatory activity (Figure 3, (B)-(E)). In summary, PN06 at concentrations below 40 μM is non-cytotoxic to normal human THP1 cells and exhibits anti-inflammatory activity.

[0085] [3.2 LPS] [Induced inflammatory response] [ ]

[0086] In this embodiment, LPS was used to induce an inflammatory response in mouse macrophage cell line (RAW 264.7 cells), followed by PN06 treatment, and the ability of PN06 to inhibit inflammatory factors was observed. The results are shown in Figure 4.

[0087] Compared to the empty vector (DMSO) treatment group, the concentrations of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α were significantly decreased in the PN06 treatment group, and the concentrations of pro-inflammatory cytokines decreased with increasing PN06 concentration (Figure 4, (A)-(C)). Furthermore, immunospot analysis revealed that, under LPS-induced inflammatory conditions, the expression levels of key regulators of liver inflammation and fibrosis, iNOS and COX2 proteins, were significantly reduced in the PN06 treatment group compared to the empty vector (DMSO) treatment group, and these protein expression levels decreased with increasing PN06 concentration (Figure 4, DE). These results indicate that PN06 significantly inhibits the expression of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α in a dose-dependent manner, and may regulate their anti-inflammatory response by inhibiting the expression of iNOS and COX2.

[0088] [3.3 LPS] [Induced] [MAPK] [Signaling pathways and downstream pro-inflammatory cytokine genes] [ ]

[0089] In this embodiment, the effects of PN06 on LPS-induced MAPK signaling pathways and the expression of downstream pro-inflammatory cytokine genes were investigated. Accordingly, THP1 cells were treated with PN06 and LPS, and cell samples were collected at different time points. Immunomodulation and real-time quantitative PCR were performed to assess the activation status of the MAPK signaling pathways (ERK, JNK, and p38) and the mRNA expression of downstream pro-inflammatory cytokine genes IL-1β, IL-6, TNF-α, and TGF-β. The results are shown in Figure 5.

[0090] Immunomodulation analysis showed that, compared to the untreated group, the PN06-treated group exhibited significantly reduced levels of phosphorylated ERK, JNK, and p-p38, as well as a significant decrease in t-ERK, t-JNK, and t-p38 (Figure 5, (A)). Further analysis using real-time quantitative PCR revealed that, compared to the empty vector (DMSO)-treated group, the PN06-treated group showed a significant decrease in the mRNA expression of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α (Figure 5, BE).

[0091] In summary, PN06 can significantly inhibit LPS-induced MAPK phosphorylation and reduce the expression of downstream pro-inflammatory cytokine genes, further confirming that PN06 has anti-inflammatory activity.

[0092] [Example] [4] [:] [PN06] [Reduce carbon tetrachloride] [(CCL4)] [Induced symptoms of liver fibrosis]

[0093] In this embodiment, the efficacy of compound PN06 on liver fibrosis was investigated. Following the steps described in the Materials and Methods section, experimental animals were induced to develop liver fibrosis with CCL4 (2 µl / g CCL4 injected intraperitoneally twice weekly), and then treated with PN06.

[0094] The results showed no significant difference in body weight between the PN06 treatment group and the DMSO-treated and CCL4-treated liver fibrosis groups (Figure 6, (B)). When the mice reached the experimental endpoint at 6 weeks of age, they were sacrificed, and their liver tissue was collected to observe liver fibrosis and inflammation. The appearance of the mouse liver tissue showed that, compared to the DMSO-treated group, the liver treated with CCL4 exhibited significant fibrosis; however, after PN06 treatment, liver fibrosis was significantly reduced (Figure 6, (C)-(D)). Further sectioning and staining of the liver tissue with Massen's trichrome staining revealed that, compared to the DMSO-treated group, the liver tissue sections treated with CCL4 showed significant inflammation and fibrosis; however, after PN06 treatment, the morphology was similar to that of the DMSO-treated group (Figure 6, (E)).

[0095] Regarding liver function indicators AST and ALT, the results showed that, compared with the DMSO control group, CCL4 induction led to a 1.72-fold and 2.12-fold increase in serum AST and ALT levels in mice, respectively. However, after PN06 treatment, AST decreased to 66% and ALT decreased to 53%, indicating that PN06 can effectively improve liver function (Figure 6, (F)).

[0096] In conclusion, PN06 can significantly reduce pathological changes such as inflammation and fibrosis in liver tissue, has the potential to inhibit the process of liver fibrosis, and effectively improve liver function.

[0097] [Example] [5] [:] [PN06] [Anti-inflammatory mechanism]

[0098] [5.1] [Whole Transcriptosome Sequencing Analysis] [(whole-transcriptome sequencing) ]

[0099] In this embodiment, whole transcriptomic sequencing analysis was used to investigate the effect of PN06 on gene expression. The results showed that in the PN06 group, the expression of 162 genes changed more than 2-fold compared with the control group (DMSO treatment) (Figure 7, (A)). Further bioinformatics analysis showed that these differentially expressed genes are mainly involved in key pathways such as the structure and remodeling of the extracellular matrix (ECM) and cytokine activation, indicating that PN06 can regulate the expression of pro-inflammatory cytokines and ECM formation, consistent with the in vitro and in vivo experimental results of other embodiments disclosed herein (Figure 7, (B)).

[0100] Furthermore, the expression levels of AXL receptor tyrosine kinase and its ligand GAS6 in the PN06 treatment group were reduced by 42% and 37%, respectively, compared to the control group (DMSO). Since the AXL-GAS6 axis is known to be closely related to the activation of human hepatic stellate cells (HSCs), these results suggest that PN06 may participate in the anti-fibrotic mechanism by regulating AXL-GAS6 signaling. To verify the results of the whole transcriptome analysis, HSCs induced by THLE-3 and TGF-β were further treated with PN06 or DMSO for 24 hours, and real-time quantitative PCR analysis was performed. The results showed that PN06 significantly reduced the expression of AXL and GAS6, further supporting its potential regulatory mechanism in anti-hepatic fibrosis (Figure 7C). In summary, PN06 has the ability to regulate inflammation-related genes and the AXL-GAS6 signaling axis, suggesting that it may exert its potential anti-hepatic fibrosis therapeutic effect by inhibiting inflammation- and fibrosis-related pathways.

[0101] [5.2] [Human hepatic stellate cells] [(HSC)] [System activation and extracellular matrix] [(ECM)] [Express]

[0102] Example 5.1 above has demonstrated that GAS6 / AXL signaling is closely related to HSC cell activation. Therefore, PN06 may inhibit HSC activation by reducing the expression of AXL and its ligand GAS6, thereby slowing down liver fibrosis. To verify this hypothesis, this example analyzed the protein expression levels of α-smooth muscle actin (α-SMA) and type I procollagen α1 (COL1A1), both of which are key markers of HSC activation. After 24 hours of PN06 treatment, the immunoblotting results of the HSC cell line showed that the expression levels of α-SMA and COL1A1 were significantly lower than those in the control group, indicating that PN06 can effectively inhibit HSC activation (Figure 8, (A)(B)). In addition, we found that PN06 treatment also significantly inhibited the activation of PI3K / AKT signaling, which is known to regulate the expression of α-SMA and COL1A1 (Figure 8, A and C).

[0103] Overall, these results show that PN06 inhibits the downstream PI3K / AKT signaling pathway by downregulating the expression of GAS6 and AXL, thereby suppressing the activation of HSCs and the expression of ECM-related genes, demonstrating its potential anti-fibrotic effect.

[0104] [5.3] [Human liver stellate cells] [(HHSteC)] [Cell cycle and apoptosis]

[0105] To further evaluate the effects of PN06 on the physiological function of HSCs, this study treated HHSteCs with different concentrations of PN06 for 24 hours, then collected the cells and performed flow cytometry analysis to assess cell cycle distribution and apoptosis rate.

[0106] The results showed that, compared with the control group, the cells in the 40 μM PN06 treatment group were mainly arrested in the S phase, and the number of cells in the sub-G1 phase was significantly increased, indicating that PN06 can inhibit the cell cycle process and induce apoptosis (Figure 9, (A)).

[0107] Furthermore, apoptosis analysis confirmed that the number of apoptotic cells in PN06 was significantly increased compared to the control group, supporting the fact that PN06 can promote HSC apoptosis (Figure 9, (B)). In summary, PN06 can effectively inhibit the survival and activation of human liver stellate cells (HHSteC) by arresting the cell cycle and inducing apoptosis, revealing its potential in the treatment of liver fibrosis.

[0108] [5.4 HSC] [activation and] [ECM] [form]

[0109] To verify whether PN06 inhibits HSC activation and delays liver fibrosis by suppressing GAS6 / AXL signaling, this study used immunohistochemical (IHC) staining to analyze the expression of marker proteins for HSC activation in the liver tissue of CCL4-treated mice. The results showed that, compared to the DMSO control group, the expression levels of α-SMA and COL1A1 in the liver tissue of mice treated with CCL4 were significantly increased. However, in the PN06 group, the expression levels of these proteins were significantly decreased (Figure 10, (A)). This indicates that PN06 effectively inhibits HSC activation and further slows down the liver fibrosis process by inhibiting AXL phosphorylation (Figure 10, (B)).

[0110] Although the above embodiments disclose specific examples of the present invention, they are not intended to limit the present invention. Those skilled in the art can make various modifications and alterations to the present invention without departing from the principles and spirit of the present invention. Therefore, the scope of protection of the present invention shall be defined by the appended claims.

[0111] none

Claims

1. The use of (24S)-3β-hydroxy-5α-stigmastan-6-one in the preparation of a medicament for treating benign prostatic hyperplasia in an individual, wherein the medicament is administered to the individual at a dose of 0.1-50 mg / kg body weight.

2. The use as described in claim 1, wherein the drug is administered to the individual at a dose of approximately 3.5 mg / kg body weight.

3. The use as described in claim 1, wherein the drug is administered to the individual three times a week.

4. The use as described in claim 2, wherein the drug further comprises an antiprostate hypertrophy drug.

5. The use as described in claim 4, wherein the antiprostate hypertrophy drug is selected from the group consisting of: Terazosin, Doxazosin, Tamsulosin, Alfuzosin, Naftopidil, Silodosin, Finasteride, and Dutasteride.

6. The use as described in claim 1, wherein the individual is a human being.

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