WO2018217237A1 - Polythérapie du cancer à l'aide de compositions végétales et d'enzalutamide - Google Patents

Polythérapie du cancer à l'aide de compositions végétales et d'enzalutamide Download PDF

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WO2018217237A1
WO2018217237A1 PCT/US2018/000120 US2018000120W WO2018217237A1 WO 2018217237 A1 WO2018217237 A1 WO 2018217237A1 US 2018000120 W US2018000120 W US 2018000120W WO 2018217237 A1 WO2018217237 A1 WO 2018217237A1
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enzalutamide
cancer
botanical
botanical composition
extract
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PCT/US2018/000120
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English (en)
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James Dao
Jeffrey Dao
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Genyous Biomed International
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Priority to EP18805621.2A priority Critical patent/EP3630090A4/fr
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    • 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
    • A61K36/074—Ganoderma
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
    • 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
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
    • A61K36/537—Salvia (sage)
    • 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
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
    • A61K36/539—Scutellaria (skullcap)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/46—Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions

Definitions

  • This invention relates generally to the field of compositions for treatment of cancer. More specifically, the invention provides multifunctional, multitargeted compositions of botanical extracts in combination with enzalutamide for the prevention and therapy of cancer, and specifically prostate cancer.
  • prostate cancer is the most common cancer in American men.
  • the American Cancer Society's estimates for prostate cancer in the United States for 2017 are: about 161,360 new cases of prostate cancer; and about 26,730 deaths from prostate cancer.
  • About 1 man in 7 will be diagnosed with prostate cancer during his lifetime.
  • Prostate cancer develops mainly in older men.
  • About 6 cases in 10 are diagnosed in men aged 65 or older, and it is rare before age 40.
  • Prostate cancer is the third leading cause of cancer death in American men, behind lung cancer and colorectal cancer.
  • About 1 man in 39 will die of prostate cancer.
  • prostate cancers are slow growing; however, there are cases of aggressive prostate cancers.
  • the cancer cells may metastasize (spread) from the prostate tu ulher parts of the body, particularly the bones and lymph nodes.
  • Prostate cancer may cause pain, difficulty in urinating, problems during sexual intercourse, or erectile dysfunction. Other symptoms can potentially develop during later stages of the disease.
  • Treatment options for prostate cancer with intent to cure are primarily surgery, radiation therapy, and proton therapy.
  • Other treatments such as hormonal therapy, chemotherapy, cryosurgery, and high intensity focused ultrasound (HIFU) also exist, depending on the clinical scenario and desired outcome.
  • HIFU high intensity focused ultrasound
  • Enzalutamide is an orally bioavailable, organic, non-steroidal small molecule targeting the androgen receptor (AR) with potential antineoplastic activity. Through a mechanism that is reported to be different from other approved AR antagonists, enzalutamide inhibits the activity of prostate cancer cell ARs, which may result in a reduction in prostate cancer cell proliferation and, correspondingly, a reduction in the serum prostate specific antigen (PSA) level. AR over- expression in prostate cancer represents a key mechanism associated with prostate cancer hormone resistance
  • Enzalutamide is marketed by Astellas Pharma Inc. with the brand name XTANDI ® . It is recommended in combination with a luteinizing hormone-releasing hormone analog or surgical castration.
  • XTANDI (enzalutamide) capsules are indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC).
  • compositions of botanicals comprising therapeutically effective amounts of two or more of an extract of Ganoderma lucidum, an extract of Salvia miltlorrhiza and an extract of
  • the present invention relates to combinations of enzalutamide and compositions botanical extracts for treatment and theraopy of prostate cancer.
  • compositions of botanical extracts can be used to reduce or alleviate the side affects when used with standard non-botanical chemotherapies. Side effects are reduced by inhibiting inflammatory responses, modulating immune responses, reducing oxidative stress, modulating immune responses, inhibiting viral and microbial infections, modulating cell proliferative responses or other biological responses.
  • the compositions of the invention may also alleviate side affects of standard therapeutic agents by balancing general biological responses against perturbations in specific biological pathways due to treatment with the therapeutic agent.
  • the composition comprises combinations of two or more extracts of Ganoderma lucidum, Scutellaria barbata, Scutellaria baicalensis, Salvia miltiorrhiza, and optionally, Hippophae rhamnoides (sea buckthorn).
  • this method comprises treatment or therapy of prostate cancer in a human is provided, the method comprising: administering an effective amount of a botanical composition that is effective for reducing androgen receptor protein expression; and
  • Botanical compositions comprising non-alcoholic organic extracts of Ganoderma lucidum, Salvia miltiorrhiza, and Scutellaria barbata in conjunction with enzalutamide therapy are used.
  • Figure 1 shows the synergistic effect on inhibition of cell proliferation by a combination of AneustatTM(OMN54) and MDV3100 ® (enzalutamide) on castration-resistant prostate cell (C4- 2 cell line) growth.
  • Figure 2 shows the synergistic effect on inhibition of cell proliferation by a combination of AneustatTM(OMN54) and ENZA (MDV3100®; enzalutamide) on castration-resistant prostate cell (C4-2B MDV) growth.
  • C4-2B MDVR cells were treated with enzalutamide (ENZA) or OMN54 or their combination as indicated in FBS condition, total cell number was determined after 5 days treatment.
  • plant refers to seeds, leaves, stems, flowers, roots, berries, bark, or any other plant parts that are useful for the purposes described.
  • the underground portion of the plant such as the root and rhizoma
  • the leaves, stems, seeds, flowers, berries, bark, or other plant parts also have medicinal effects and can be used for preparing tea and other beverages, cream, and in food preparation.
  • treatment includes preventing, inhibiting, curing, or alleviating.
  • compositions are delivered to the host in such a manner that it can achieve the desired purpose.
  • compositions can be administered by an effective route, such as orally, topically, rectally, etc.
  • “Synergism” may be measured by combination index (CI).
  • the combination index method was described by Chou and Talalay. (Chou, T.-C. The median-effect principle and the combination index for quantitation of synergism and antagonism, p. 61-102. In T.-C. Chou and D. C. Rideout (ed.), Synergism and antagonism in chemotherapy. Academic Press, San Diego, Calif. (1991); Chou, T.-C, and P. Talalay. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs on enzyme inhibitors. Adv. Enzyme Regul. 22:27-55 (1984)).
  • a Cl value of 0.90 or less is considered synergistic, with values of 0.85 being moderately synergistic and values below 0.75 being significantly synergistic.
  • CI values of 0.90 to 1.10 are considered to be merely additive and higher values are antagonistic.
  • determination of synergy may be affected by biological variability, dosage, experimental conditions (temperature, pH, oxygen tension, etc.), treatment schedule and combination ratio.
  • a botanical composition drug include: bio-availability and minimal toxicity. Preferably the drug can be administered orally.
  • the botanical composition provides a combination of multiple therapeutic functions to act simultaneously and synergistically on multiple biological targets.
  • the botanical composition comprises low doses of individual therapeutic ingredients to minimize disruption of physiological homeostasis and development of drug resistance. Typically, a history of therapeutic efficacy and safety is considered in selecting nature-derived active ingredients.
  • MAPK mitogen- activated protein kinase
  • PI3K phosphoinositide 3- kinase
  • STAT Signal transducers and activators of transcription
  • p53 signaling pathway
  • Wnt Wnt signaling pathway
  • COX cyclooxygenase
  • a botanical drug suitable for cancer would include functions to affect one or more of these pathways as well as functions generally related to alleviation of cancer conditions such as anti-inflammation, immune system modulation, anti-angiogenic, anti-metastatic, and the like.
  • a botanical drug suitable for a particular type of cancer will possess functionalities that also are directed to pathways unique to a type of cancer.
  • botanical drug suitable for the treatment of prostate cancer may include functionalities related to androgen receptors.
  • the botanical drug is administered in combination with standard chemotherapy regimens to achi
  • Prostate cancer is a complex disease.
  • a number of biological pathways have been implicated in prostate cancer development: growth factor activity, cell death (apoptosis), oncogenesis, tumor suppression, cell cycle modulation, cell surface modulation, androgen receptors, co-activators & repressors.
  • Several conditions are associated with prostate disease: Benign prostate hyperplasia (BPH), prostatitis, prostatic intraepithelial neoplasia (PIN).
  • Benign prostatic hyperplasia refers to the increase in size of the prostate in middle-aged and elderly men. BPH is characterized by hyperplasia of prostatic stromal and epithelial cells, resulting in the formation of large, fairly discrete nodules in the periurethral region of the prostate. Although prostate specific antigen levels may be elevated in these patients, because of increased organ volume and inflammation due to urinary tract infections, BPH is not considered to be a premalignant lesion.
  • Alpha blockers (a 1 -adrenergic receptor antagonists) provide symptomatic relief of BPH symptoms.
  • 5a-reductase inhibitors When 5a-reductase inhibitors are used together with alpha blockers a reduction of BPH progression to acute urinary retention and surgery has been noted in patients with enlarged prostates.
  • Prostate cancer is classified as an adenocarcinoma, or glandular cancer, that begins when normal semen-secreting prostate gland cells mutate into cancer cells. Initially, small clumps of cancer cells remain confined to otherwise normal prostate glands, a condition known as carcinoma in situ or prostatic intraepithelial neoplasia (PIN). Although there is no clear evidence that ⁇ is a cancer precursor, it is closely associated with cancer.
  • Prostate specific antigen is a 34 kD glycoprotein manufactured almost exclusively by the prostate gland. Also known as kallikrein III, PSA is a serine protease. (Lilja H. (Nov 2003). "Biology of Prostate-Specific Antigen”. Urology 62 ((5 Suppl 1)): 27-33).
  • PSA is often elevated in the presence of prostate cancer and in other non-malignant prostate disorders such as BPH.
  • a blood test to measure PSA is the most effective test currently available for the early detection of prostate cancer.
  • Higher than normal levels of PSA are associated with both localized and metastatic prostate cancer (CaP).
  • CaP metastatic prostate cancer
  • PSA levels can change for many reasons other than cancer. Two common causes of high PSA levels in the absence of cancer are enlargement of the prostate (benign prostatic hypertrophy (BPH)) and infection in the prostate (prostatitis).
  • PSA is not a perfect test. Some men with prostate cancer do not have an elevated PSA, and most men with an elevated PSA do not have prostate cancer. Short of biopsy, no noninvasive tests provide a clear diagnosis of prostate cancer. Enzalutamide
  • Enzalutamide brand name Xtandi
  • NSAA non-steroidal antiandrogen
  • Enzalutamide is clinically active in metastatic castration-resistant prostate cancer.
  • PSA level decreased more than 50% in 40 of 65 chemo-naive patients and 38 of 75 chemotherapy- treated patients.
  • Median time to radiographic progression was 56 weeks for chemo-naive patients and 25 weeks for the post-chemotherapy population.
  • Enzalutamide is a diarylthiohydantoin derivative, and is structurally related to earlier NSAAs such as flutamide, nilutamide, and bicalutamide. However, unlike the first-generation NSAA bicalutamide, enzalutamide does not promote translocation of AR to the cell nucleus and in addition prevents binding of AR to deoxyribonucleic acid (DNA) and AR to coactivator proteins. (Tran C. et al., Science. 324 (5928): 787-90 (2009)). As such, it has been described as an AR signaling inhibitor in addition to antagonist. (Antonarakis ES (June 2013). Translational Andrology and Urology. 2 (2): 1 19-120).
  • LNCaP cells a prostate cancer cell line
  • AR an antigen-specific peptide
  • VCaP cells which over-express the AR
  • enzalutamide induced apoptosis whereas bicalutamide did not.
  • enzalutamide behaves as an antagonist of the W741C mutant AR in contrast to bicalutamide which behaves as a pure agonist when bound to the W741C mutant.
  • Enzalutamide has only 2- to 3-fold lower affinity for the AR relative to the endogenous ligand dihydrotestosterone (DHT). Enzalutamide is reported to be a strong inducer of the enzyme CYP3A4 and a moderate inducer of CYP2C9 and
  • Enzalutamide has approximately 5- to 8-fold higher binding affinity for the androgen receptor (AR) compared to bicalutamide. As such, it has been described as an AR signaling inhibitor in addition to antagonist. Enzalutamide has only 2- to 3-fold lower affinity for the AR relative to the endogenous ligand dihydrotestosterone (DHT).
  • AR androgen receptor
  • DHT endogenous ligand dihydrotestosterone
  • Enzalutamide is regarded as having a moderate negative effect on sexual function and activity, significantly less than that of GnRH analogs but similar to that of other NSAAs such as bicalutamide. Enzalutamide is regarded as having a moderate negative effect on sexual function and activity, significantly less than that of GnRH analogues but similar to that of other NSAAs such as bicalutamide.
  • the enzalutamide is provided as 40 mg capsules and 160 mg (four 40 mg capsules) are administered daily, with or without food.
  • a botanical formulation presents an optimal first line therapy when high PSA levels are detected.
  • Botanical compositions such as those disclosed herein, have very low toxicity and yet are effective against prostate cancer.
  • the botanical composition was designed following demonstration of a number of desirable functions among the ingredients and in the assembled composition.
  • a number of therapeutically active chemical entities are present in Ganoderma lucidum (#9), Scutellaria barbata (#15), and Salvia miltiorrhiza ⁇ #14): ganoderic acid H, crytotanshinone, tanshinone IIA, scutellarin tetramethyl ether, scutellarin, apigenin and wogonin.
  • a number of chemical entities are present in the botanical composition: adenosine, ganoderic acid A, oleic acid, tanshinone IIA, scutellarin, apigenin, luteolin, and wogonin. Each of these chemical entities is known to demonstrate one or moic of anti-viral, anti-inflammatory, immune modulatory, anti-angiogenic and anti-cancer/metastatic functions.
  • OMN54 An exemplary combination of Ganoderma lucidum (#9), Scutellaria barbata (#15), and Salvia miltiorrhiza (#14) was designated OMN54, based on the synergism displayed by certain combinations of extracts of the three botanicals when each botanical is between 1% w/w and 90% w/w of the combined composition. Extracts of the botanicals were preferably made in organic medium, such as alcohol, and non-alcoholic media including ester, lipid and the like. In a preferred embodiment the extracts were made in ethyl acetate medium.
  • Ganoderma lucidum at 33-50% w/w More specifically the Ganoderma lucidum extract is selected from 33%, 35%, 40%, 42%, 44%, 45%, 46%, 46.5%, 47%, 47.5%, 48%, 48.5%, 49%, 49.5% and 50%.
  • Scutellaria barbata at 33-50% w/w. More specifically the Scutellaria barbata extract is selected from 33%, 35%, 40%, 42%, 44%, 45%, 46%, 46.5%, 47%, 47.5%, 48%, 48.5%, 49%, 49.5% and 50%.
  • Salvia miltiorrhiza at 1-10% w/w. More specifically the Salvia miltiorrhiza extract is
  • OMN54 did not modulate pro-inflammatory proteins in unstimulated PBMC (suggesting safety for long-term use). In the presence of inflammatory stimulus (PHA mitogen), OMN54 suppressed inflammatory signaling (significant antiinflammatory activity). The effect of OMN54 in stimulated and unstimulated cells was observed for a number of proteins comprising cytokines, chemokines and growth factors.
  • the human prostate cancer cell line, LNCaP, is androgen sensitive and PSA positive.
  • OMN54 was tested for activity on LNCaP cell line, on the expression of specific genes associated with prostate cancer. High levels of Prostate Specific Antigen (PSA) are associated with prostate cancer. The significant suppression of the PSA transcript by OMN54 is considered beneficial in the treatment of prostate cancer.
  • PSA Prostate Specific Antigen
  • OMN54 displays profound antiproliferative effect on prostate cancer cells, inducing the apoptosis of both androgen receptor (AR)-positive (LNCaP) and AR-negative (DU-145) prostate cancer cell lines. OMN54 also displays NF-kappa B inhibition. The anti-inflammatory and antiproliferative functions displayed by the botanical composition also are effective against BPH. Thus, following detection of high PSA levels and prior to invasive tests for diagnosis of cancer, a low toxicity botanical formulation which is effective against both BPH and neoplastic states like prostate cancer and PIN, provides a promising regimen for first intervention.
  • capsaicin found in red peppers, which has a profound anti-proliferative effect on human prostate cancer cells in culture and in mouse xenografts.
  • capsaicin down- regulates PSA expression by direct inhibition of PSA transcription mediated by inhibition of NF- kappa B activation by preventing its nuclear migration.
  • Botanicals are a valuable resource for the discovery and development of novel, naturally derived agents to treat human disease.
  • Botanical extracts usually comprise multiple molecules and possess multiple functions useful in the treatment and prevention of disease.
  • Botanical extracts also can function to maintain normal tissue homeostasis by affecting multiple biological pathways such as the inflammatory pathway, the immune response pathway and the oxidative stress response pathway.
  • botanical extracts can alleviate the harmful side effects of many therapeutic agents used to treat multiple disease targets.
  • Botanicals have been demonstrated to be a successful source of anticancer compositions.
  • Examples include Gynostemma pentaphyllum extract, Camellia sinensis (green tea) and
  • Crataegus pinnatifida (hawthorn berries) and a method of making the same are the subject of U.S. Pat. Nos. 5,910,308 and 6, 168,795.
  • Some drugs, derived from plants that are currently used in cancer therapy were designed to perturb microtubule shortening (depolymerization) or lengthening (polymerization), such as paclitaxel, docetaxel, etoposide, vincristine, vinblastine, and vinorelbine (Compton, D. A., et al., (1999) Science 286:913-914). They share a common mechanism of action of binding to tubulin, the molecule of which microtubules are composed. (Compton, D.
  • compositions comprising botanical extracts to treat human diseases that are associated with multiple biological pathways in their pathologies.
  • compositions of the invention are comprised of two or more botanical extracts which work synergistically to modulate multiple biological pathways including but not limited to
  • Ganoderma lucidum suggests that Ganoderma lucidum has anti-inflammatory activity.
  • Ganoderma lucidum is preferred, one skilled in the art would recognize that other species of Ganoderma may also be used in the present invention.
  • G. tsugae has been shown to modulate Thl/Th2 and macrophage responses in allergic murine model, and recombinantly expressed fungal immunomodulatory protein, FlP-gts, from G. tsugae inhibited telomerase activity in A549 human lung adenocarcinoma cell line (Lin, J.Y. et al., (2006) Food Chem. Toxicol.; Liao, C.H. et al., (2006) Mo. Carcinog. 45(4):220-9).
  • Ganoderma examples include, but are not limited to, G. applanatum, G. mongolicum, G. microsporum, G. subamboinense, G. pfeifferi, G. meredithae, G. oregonense (G. oregonse), G. resinaceum, G. oerstedii, G. ungulatum, G. mirabile, G. tsugae, G. sessile, G. valesiacum, G.fornicatum, G. carnosum, G. australe, and G. boninense.
  • Scutellaria barbata Scutellaria barbata, a traditional Chinese medicine for liver, lung and rectal tumors, has been shown to inhibit mutagenesis, DNA binding and metabolism of aflatoxin B 1 (AFB 1) and cytochrome P450-linked aminopyrine N-demethylase (Wong B.Y. et al, (1993) Eur. J. Cancer Prev. 2(4):351-6; Wong B.Y. et al., (1992) Mutat. Res. 279(3):209- 16). Scutellaria barbata is also capable of enhancing macrophage function in vitro and inhibiting tumor growth in vivo (Wong B.Y. et al., (1996) Cancer Biother. Radiopharm. l l(l):51-6).
  • This herb contains vitamins C and E as well as calcium, potassium, magnesium, iron, zinc scutellarin, volatile oil, tannin and bitter principles.
  • the scutellarin acts on the central nervous system. Scutellarin, an active ingredient from Scutellaria barbata has been purified by liquid chromatography (Wenzhu Zhang et al., (2003) J. of Liquid Chromatography & Related Technologies 26 (13):2133-40).
  • Scutellaria baicalensis Scutellaria baicalensis has been shown to have antiproliferative and apoptotic activities against lymphocytic leukemia, lymphoma, and myeloma cell lines and possess anti-cancer activity on human malignant brain tumor cells (Kumagai, T. et al. (2006) Leuk. Res.; Scheck, A.C. et al., (2006) BMC Complement Altern. Med. 6:27).
  • Scutellaria barbata should not be confused with Scutellaria baicalensis.
  • Scutellaria barbata and Scutellaria baicalensis are preferred, one skilled in the art would recognize that other species of Scutellaria may also be used in the present invention.
  • Scutellaria radix has been shown to suppress ethanol-induced caspase-11 expression and cell death in N(2)a cells, and Baicalein, a component of Scutellaria radix, leads to suppression of proliferation and induction of apoptosis in human myeloma cells (Kang, K. et al., (2005) Brain Res. Mol. Brain Res. 142(2): 139-45; Ma, Z. et al. (2005) Blood 105(8):3312-8).
  • Scutellaria amabilis include, but are not limited to, Scutellaria amabilis,
  • Salvia miltiorrhiza has been shown to lower cholesterol, reduce endothelial damage and to inhibit lipid peroxidation in hypercholesterolemic animals. This inhibition of oxidation of LDL may reduce atherosclerosis (Wu Y.J. et al., (1998) Arteriosclerosis Thromb Vase Biol 18:481-6).
  • a Salvia miltiorrhiza constituent has been found to inhibit noradrenalin-induced contraction of the aortic strips through reduction in Ca 2+ mobilization. This vasodilatory activity may explain the traditional use of Salvia miltiorrhiza in hypertension (Nagai M. et al., Biol Pharm Bull (1996) 19:228-32).
  • Salvia miltiorrhiza has been shown to have a markedly superior effect to nitroglycerin, with a more persistent action and better improvement of cardiac function (Bai, Y.R. and Wang, S.Z., (1994) Zhongguo Zhong Xi Yi Jie He Za Zhi 14:24-5, 4).
  • Hippophae rhamnoides (sea buckthorn): Sea buckthorn seed oil contains a high content of the two essential fatty acids, linoleic acid and a-linolenic acid, which are precursors of other polyunsaturated fatty acids such as arachidonic and eicosapentaenoic acids.
  • the oil from the pulp/peel of seabuckthorn berries is rich in palmitoleic acid and oleic acid (Chen et al., "Chemical composition and characteristics of seabuckthorn fruit and its oil.” Chem. Ind. Forest Prod. (Chinese) 10 (3), 163-175).
  • the increase in the level of ⁇ -linolenic acid in plasma lipids showed a clear improving effect on AD symptoms (Yang et al., (2000) J. Nutr Biochem.
  • Camellia sinensis (Green tea): Dried leaves from the Camellia sinensis plant is processed into three types of tea: oolong tea, black tea, and green tea.
  • Green tea extract is a bioflavonoid-rich, potent extract which is used primarily for fighting free radicals. It has a high content of polyphenols, which are a type of bioflavonoids.
  • polyphenols which are a type of bioflavonoids.
  • the tea leaves are stabilized by moist or dry heat which destroys the enzyme polyphenoloxidase and thus, prevents oxidation of polyphenols. These polyphenols are the main biologically active ingredients in green tea.
  • the green tea is Dragon Well tea or Lung Ching tea.
  • EGCG epigallocatechin
  • epicatechin-3-gallate epigallocatechin
  • compositions of the present invention can be in any form which is effective, including, but not limited to dry powders, grounds, emulsions, extracts, and other conventional compositions.
  • a suitable solvent such as water, alcohol, methanol, mixed solvents, or any other solvents.
  • the choice of the solvent can be made routinely, e.g., based on the properties of the active ingredient that is to be extracted or concentrated by the solvent.
  • Preferred active ingredients of the compositions crenulata include, but are not limited to, salidroside, tyrosol, ⁇ -sitosterol, gallic acid, pyrogallol, crenulatin, rhodionin, and/or rhodiosin.
  • These ingredients can be extracted in the same step, e.g., using an alcoholic solvent, or they may be extracted individually, each time using a solvent which is especially effective for extracting the particular target ingredient from the plant.
  • extraction can be performed by the following process: Milling the selected part, preferably root, to powder. The powder can be soaked in a desired solvent for an amount of time effective to extract the active agents from the compositions.
  • compositions of the present invention can be administered in any form by any effective route, including, e.g., oral, parenteral, enteral, intraperitoneal, topical, transdermal (e.g., using any standard patch), ophthalmic, nasally, local, non-oral, such as aerosol, inhalation, subcutaneous, intramuscular, buccal, sublingual, rectal, vaginal, intra-arterial, and intrathecal, etc. It can be administered alone, or in combination with any ingredient(s), active or inactive, including in a medicinal form, or as a food or beverage additive.
  • any effective route including, e.g., oral, parenteral, enteral, intraperitoneal, topical, transdermal (e.g., using any standard patch), ophthalmic, nasally, local, non-oral, such as aerosol, inhalation, subcutaneous, intramuscular, buccal, sublingual, rectal, vaginal, intra-arterial, and intrathecal, etc. It can be administered alone,
  • compositions are administered orally in any suitable form, including, e.g., whole plant, powdered or pulverized plant material, extract, pill, capsule, granule, tablet or a suspension.
  • compositions can be combined with any pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carriers any pharmaceutical carrier, such as the standard carriers described, e.g., Remington's Pharmaceutical Science, 18th Edition, Mack Publishing company, 1990.
  • suitable carriers are well known in the art and can include, but are not limited to, any of the standard pharmaceutical carriers such as a phosphate buffered saline solutions, phosphate buffered saline containing Polysorb 80, water, emulsions such as oil/water emulsion and various types of wetting agents.
  • Other carriers may also include sterile solutions, tablets, coated tablets pharmaceutical and capsules.
  • Such carriers typically contain excipients such as starch, milk, sugar, certain types of clay, gelatin, stearic acid or salts thereof, magnesium or calcium stearate, talc, vegetable fats or oils, gums, glycols.
  • excipients such as starch, milk, sugar, certain types of clay, gelatin, stearic acid or salts thereof, magnesium or calcium stearate, talc, vegetable fats or oils, gums, glycols.
  • Such carriers can also include flavor and color additives or other ingredients.
  • Compositions comprising such carriers are formulated by well known conventional methods. Generally excipients formulated with the compositions are suitable for oral administration and do not deleteriously react with it, or other active components.
  • Suitable pharmaceutically acceptable carriers include but are not limited to water, salt solutions, alcohols, gum arabic, vegetable oils, benzyl alcohols, gelatin, carbohydrates such as lactose, amylose or starch, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxy
  • additives include, e.g., antioxidants and preservatives, coloring, flavoring and diluting agents, emulsifying and suspending agents, such as acacia, agar, alginic acid, sodium alginate, bentonite, carbomer, carrageenan, carboxymethylcellulose, cellulose, cholesterol, gelatin, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, octoxynol 9, oleyl alcohol, povidone, propylene glycol monostearate, sodium lauryl sulfate, sorbitan esters, stearyl alcohol, tragacanth, xanthan gum, and derivatives thereof, solvents, and miscellaneous ingredients such as microcrystalline cellulose, citric acid, dextrin, dextrose, liquid glucose, lactic acid, lactose, magnesium chloride, potassium metaphosphate, starch, and the like.
  • the botanical compositions can also be formulated with other active ingredients, such as anti-oxidants, vitamins (A, C, ascorbic acid, B's, such as B l, thiamine, B6, pyridoxine, B complex, biotin, choline, nicotinic acid, pantothenic acid, B 12, cyanocobalamin, and/or B2, D, D2, D3, calciferol, E, such as tocopherol, riboflavin, K, Kl, K2).
  • active ingredients such as anti-oxidants, vitamins (A, C, ascorbic acid, B's, such as B l, thiamine, B6, pyridoxine, B complex, biotin, choline, nicotinic acid, pantothenic acid, B 12, cyanocobalamin, and/or B2, D, D2, D3, calciferol, E, such as tocopherol, riboflavin, K, Kl, K2).
  • Preferred compounds include, e.
  • Enzyme Q10 Enzyme Q10, NADH, NAD, D-ribose, amino acids such as L-glutamine, Lysine, chrysin; pre- hormones such as 4-androstenedione, 5-androstenedione, 4(or 5-)androstenediol, 19-nor-4 (or 5- )-androstenedione, 19-nor-4 (or 5-)-androstenediol, Beta-ecdysterone, and 5-Methyl-7-Methoxy Isoflavone.
  • pre- hormones such as 4-androstenedione, 5-androstenedione, 4(or 5-)androstenediol, 19-nor-4 (or 5- )-androstenedione, 19-nor-4 (or 5-)-androstenediol, Beta-ecdysterone, and 5-Methyl-7-Methoxy Isoflavone.
  • Preferred active ingredients include, e.g., pine pollen, fructus lycii, Hippophae rhamnoides, Ligusticum, Acanthopanax, Astragalus, Ephedra, codonopsis, polygola tenuifolia Willd, Lilium, Sparganium, ginseng, panax notogiseng, Garcinia, Guggle, Grape Seed Extract or powder, and/or Ginkgo Biloba.
  • compositions of the present invention includes those mentioned in various text and publications, e.g., E.S. Ayensu, Medicinal Plants of West Africa, Reference Publications, Algonac, Mich. (1978); L. Boulos, Medicinal Plants of North Africa, Reference Publications Inc., Algonac, Mich. (1983); and N. C. Shah, (1982) J. Ethnopharm, 6:294-5.
  • a botanical formulation may comprise biologies and chemical entities, in addition to or in the place of, botanical extracts.
  • biologies that may comprise a botanical composition include but are not limited to blood and blood products, cells, tissues and organs, gene therapy vectors, viral and bacterial vaccines, therapeutic products produced through biotechnology such as antibodies, monoclonal antibodies, and the like.
  • a preferred composition of the present invention comprises, about 1%-100%, preferably about 20-70% of the botanical extract and, optionally, a pharmaceutically-acceptable excipient.
  • Another preferred composition of the present invention comprises, about l%-99%, preferably about 20-70% of botanical extracts, 0.1-99%, preferably 1-10% of one or more pharmaceutically active agents and, optionally, a pharmaceutically-acceptable excipient.
  • the instant invention relates to the administration of enzalutamide and the botanical compositions (such as OMN54) concurrently.
  • the botanical composition is administered simultaneously, or the same day, or within 24 hours of
  • the botanical composition and enzalutamide is formulated as a tablet dosage form comprising: a) a first part comprising a capsule of enzalutamide, wherein the capsule is formulated with one or more other pharmaceutically acceptable excipients; and b) a second part comprising a composition comprising two or more extracts of Ganoderma lucidum, Scutellaria barbata, Scutellaria baicalensis, Salvia miltiorrhiza, and optionally other pharmaceutically acceptable excipients.
  • the dosage form comprises a bilayered dosage form.
  • the dosage form is coated with one or more enteric polymers, pharmaceutically acceptable seal coat polymers or rate controlling polymers.
  • the two active ingredients are provided as a dispersion provided in a single capsule, granule, mini-tablet or tablet form.
  • enzalutamide and/or the botanical extracts composition are present in an immediate release, delayed release, sustained release, extended release, controlled release or modified release form.
  • the botanical extracts are formulated with excipients comprising one or more of an emulsifying agent, an antioxidant and a diluent.
  • the emulsifying agent is one or more of Cremophor EL, oleic acid and labrasol; the antioxidant is selected from ascorbic acid and alpha tocopherol; and the diluent is soya oil.
  • the invention relates to a kit containing separate dosage forms for each active ingredient, for example, comprising enzalutamide provided in a capsule form and the botanical extracts provided in a second capsule form.
  • the capsule and the tablet are provided in a single package (such as a blister pack).
  • Amounts are selected based on various factors, including the milieu to which the virus is administered (e.g., a patient with cancer, animal model, tissue culture cells, etc.), the site of the cells to be treated, the age, health, gender, and weight of a patient or animal to be treated, etc.
  • the liquid, pharmaceutically active formulation comprises a pharmaceutically active botanical composition in a liquid diluent or carrier.
  • the active ingredient may be dissolved or dispersed in the liquid diluent or carrier, which may be a water miscible or water immiscible medium.
  • liquid diluents or carriers include the following three classes: (a) Water miscible carriers: Propylene Glycol, Polyethylene Glycol, Water, Solketal, Glycofurol,
  • Dimethylisosorbide Nonionic surface active agents
  • Oils and Organic carriers Fractionated Coconut Oil, Sesame Oil, Soya Bean Oil, Vegetable Oil, Liquid Paraffin, Isopropylmyristate, Triacetin
  • Semi-solid carriers High molecular weight polyethylene glycols, and White soft paraffin.
  • one or more emulsifiers or surfactants are included in the formulation.
  • Suitable emulsifiers which can be used include one or more of fatty acids such as oleic acid, polyoxyethylene glycerol esters of fatty acids, such as Tagats; polooxylated castor oil, ethylene glycol esters, such as glycol stearate and distearate; propylene glycol esters, such as propylene glycol myristate; glyceryl esters of fatty acids, such as glyceryl stearates and monostcarates; sorbitan esters, such as spans and tweens; polyglyceryl esters, such as polyglyceryl 4-oleate; fatty alcohol ethoxylates, such as Brij type emulsifiers; ethoxylated propoxylated block copolymers, such as poloxamers; polyethylene glycol esters of fatty acids, such as Tagats; pol
  • compositions of the present invention comprise effective amounts of a combination of two or more extracts of Ganoderma lucidum, Scutellaria barbata, Scutellaria baicalensis, Salvia miltiorrhiza, and optionally, Hippophae rhamnoides (sea buckthorn) that exhibit synergy.
  • the botanical composition comprises effective amounts of extracts of Ganoderma lucidum, Scutellaria barbata, and Salvia miltiorrhiza.
  • the dosage of the composition can be readily determined by one of skill in the art based on the effective concentrations of compositions shown to display the various properties described herein.
  • compositions comprising different ratios of the individual extracts can similarly be determined.
  • a composition may exhibit anti-inflammatory effects at one concentration or ratios of combinations of extracts and varying degrees of cytotoxic effects at other concentrations or ratios of combinations of extracts.
  • Any ratio of extracts of two or more of Ganoderma lucidum, Scutellaria barbata, Scutellaria baicalensis, and Salvia miltiorrhiza can be used in the compositions of the invention. It is preferred that each extract is present in the composition in equal amounts or at about 1 % to about 90% of the total composition.
  • a particular extract comprises at least 1 %, 1.5%, 2%, 5%, 10%, 15%, 25%, 33%, 40%, 45%, 47.5%, 48.5%, 49.5%, 50%, 60%, 66%, 75%, 90% or 98% by weight of the composition.
  • the OMN54 comprises about 1-3% Salvia miltiorrhiza, and approximately equal amounts (45-50%) of Scutellaria barbata and Ganoderma lucidum.
  • compositions of the present invention comprise botanical compounds that are useful in compositions to be administered in conjunction with therapeutic agents for the treatment of disease. These compositions exhibit synergistic action with the therapeutic agent based on their anti-inflammatory, antioxidant, immune modulating, antiviral, antibacterial, antiproliferative activity or any combination of activities thereof.
  • compositions demonstrate antioxidant activity which prevents damage to chromosomes/genes, reduces effect of mutagens, alleviates side-effects of chemotherapeutic agents, alleviates side-effects of hormone therapeutic agents, and enhances cell repair mechanisms.
  • compositions further demonstrate immune system boosting activity which facilitates elimination of (i) damaged cells or (ii) cells with damaged genes. Further, the compositions provide general benefits of improving immune condition (passive immunotherapy).
  • the botanical compositions demonstrate the ability to enhanced cell cycling which could make the botanical composition of the invention a powerful adjuvant to chemotherapy (e.g., with enzalutamide), hormonal therapy, or radiation therapy by increasing effectiveness and reducing necessary dosages of chemotherapeutic agents and hormone therapeutic agents.
  • IC 50 based compositions can be standardized based on specific activities of defined properties.
  • compositions of the invention show mostly cytostatic effect with very weak cytotoxic effects in the compositions of the invention. Histopathology of cells treated with the compositions of the invention indicates minimal retention of dead cancer cells which enhance recovery following cancer therapy.
  • compositions of the invention may include, optionally, Panax Quinquefolium (Western ginseng), Camellia sinensis (green tea), and Hippophae rhamnoides (sea buckthorn).
  • prostate cancer in vivo models may be used.
  • CaP xenografts in mice may be utilized.
  • a Pten knockout mouse strain in which heterozygous mice develop tumors of the uterus, prostate, thyroid, colon, and adrenal medulla, may be obtained from the Mouse Models of Human Cancers Consortium (Podsypanina K. et al., (1999) Proc. Nat'l Acad. Sci. USA 96: 1563-1568).
  • compositions of the present invention may be administered as dried herbs.
  • Botanical preparations contain phytochemicals some of which are soluble in aqueous media while others are relatively more soluble in organic (alcohol, lipid) media.
  • Different extraction methods were used and tested for the ability to extract effective ingredients from the herbs. Extraction methods include: Aqueous (hot water) extraction; Organic (lipid fraction) extraction; non-alcoholic organic (ethyl acetate) extraction; and alcohol (ethanol) Extraction.
  • Products are prepared from herbs or herb blends by extraction with solvent (hot water, 80% ethanol, or ethyl acetate) under reflux for 30-60 minutes, separated by filtration to obtain a filtrate, and air dried for further analysis. The filtrates were combined, diluted or concentrated prior to determination of activities.
  • solvent hot water, 80% ethanol, or ethyl acetate
  • Example 2 Effect of treatment with a combination of OMNS4 with MDV3100 ®
  • OMN54 is more effective than MDV in term of cell killing in vitro. This may be due to the following: MDV3100 specifically targets AR, while OMN54 targets multiple pathways including AR, IL-6, Stat3, Akt, etc.
  • the unit for OMN54 is microgram.
  • OMN50 is 50 ⁇ g and OMN100 is 100 ⁇ g.
  • the data showed that there is a synergistic effect when OMN54 is combined with MDV at 40 microM. No additive effect was observed when MDV is at 20 ⁇ or below. Therefore, the data of MDV10. 20 microM shown here is necessary to document that there is no additive effect at these doses when combined with OMN54.
  • the ones with red circle are the data showing synergistic effect.
  • Example 3 Establishment of a human prostate cancer tissue xenograft/mouse model
  • Xenografts of human prostate cancer cell line DU145 were grown in vivo.
  • One of two tissue xenografts grew to the size of a walnut. Tumors are grafted to the renal site survive and retain their original histopathology and differentiation marker profile, even after serial passages.
  • the prostate cancer tissue very rapidly grows in SCID mice with a doubling time about 5 days.
  • Cytogenetic analyses show some abnormal chromosomes. Not only are there translocations, there are also deletions and duplication of chromosomal segments (Note: since each chromosome has its own display color, more than one color along the length of a chromosome indicates a translocation).
  • the Spectral Karyotyping (SKY) analysis shows that the tissue of a DU145 cancer xenograft contained only a low number of karyotypic alterations, although the cancer is highly advanced.
  • OMN54 significantly inhibited growth of DU145 (andro gen-independent) human prostate cancer tumors in vivo. Importantly, this effect on tumor volume was comparable to that of standard chemotherapy which is associated with significant toxicities to patients.
  • Example 5 In vivo anti-prostate tumor activity assay
  • TUNEL assay detects apoptosis-induced DNA fragmentation through a quantitative fluorescence assay.
  • Terminal deoxynucleotidyl transferase catalyzes the incorporation of bromo-deoxyuridine (BrdU) residues into the fragmenting nuclear DNA at the 3'-hydroxyl ends by nicked end labeling.
  • a TRITC-conjugated anti-BrdU antibody can then label the 3'-hydroxyl ends for detection.

Abstract

L'invention concerne des compositions végétales comprenant des extraits organiques non alcooliques de Ganoderma lucidum, de Salvia miltiorrhiza, et de Scutellaria barbata destinées à être utilisées conjointement avec de l'enzalutamide pour la thérapie du cancer. L'invention concerne également des méthodes de traitement ou de thérapie d'un cancer de la prostate chez un humain, la méthode comprenant : l'administration d'une quantité efficace d'une composition végétale qui est efficace pour réduire l'expression de protéines du récepteur des androgènes; et l'administration simultanée d'une quantité efficace d'enzalutamide, l'administration simultanée de l'enzalutamide et de la composition végétale permettant d'obtenir un meilleur effet thérapeutique qu'avec seulement l'un des deux agents.
PCT/US2018/000120 2017-05-26 2018-05-30 Polythérapie du cancer à l'aide de compositions végétales et d'enzalutamide WO2018217237A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110643582A (zh) * 2019-09-29 2020-01-03 浙江工业大学 一种从沙棘鲜果中提取sod的方法
WO2022040365A1 (fr) * 2020-08-18 2022-02-24 Curators Of The University Of Missouri Compositions et méthodes de traitement comprenant des bactéries ciblant des tumeurs et un agent de chimiothérapie ou d'immunothérapie
CN117064899A (zh) * 2023-10-13 2023-11-17 暨南大学附属第一医院（广州华侨医院） 灵芝酸a在制备治疗去势抵抗性***癌的药物中的应用

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050196409A1 (en) * 2003-09-24 2005-09-08 James Dao Compositions of botanical extracts for treating malignancy-associated changes
US20160038511A1 (en) * 2013-08-12 2016-02-11 Tokai Pharmaceuticals, Inc. Biomarkers for treatment of neoplastic disorders using androgen-targeted therapies
US20160143971A1 (en) * 2013-06-03 2016-05-26 Genyous Biomed International Combination therapy for prostate cancer using botanical compositions and docetaxel
WO2016179002A1 (fr) * 2015-05-01 2016-11-10 The Regents Of The University Of California Compositions et procédés de traitement de cancer
WO2017063562A1 (fr) * 2015-10-15 2017-04-20 华东师范大学 Combinaison de composés issus de la médecine traditionnelle chinoise et son application à la résistance au cancer de la prostate

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2816855A1 (fr) * 2010-11-04 2012-05-10 Jeffrey Dao Multitherapie pour le cancer de la prostate utilisant des compositions vegetales et du bicalutamide
US9314473B2 (en) * 2011-02-03 2016-04-19 Pop Test Oncology Limited Liability Company System and method for diagnosis and treatment

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050196409A1 (en) * 2003-09-24 2005-09-08 James Dao Compositions of botanical extracts for treating malignancy-associated changes
US20160143971A1 (en) * 2013-06-03 2016-05-26 Genyous Biomed International Combination therapy for prostate cancer using botanical compositions and docetaxel
US20160038511A1 (en) * 2013-08-12 2016-02-11 Tokai Pharmaceuticals, Inc. Biomarkers for treatment of neoplastic disorders using androgen-targeted therapies
WO2016179002A1 (fr) * 2015-05-01 2016-11-10 The Regents Of The University Of California Compositions et procédés de traitement de cancer
WO2017063562A1 (fr) * 2015-10-15 2017-04-20 华东师范大学 Combinaison de composés issus de la médecine traditionnelle chinoise et son application à la résistance au cancer de la prostate

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP3630090A4 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110643582A (zh) * 2019-09-29 2020-01-03 浙江工业大学 一种从沙棘鲜果中提取sod的方法
WO2022040365A1 (fr) * 2020-08-18 2022-02-24 Curators Of The University Of Missouri Compositions et méthodes de traitement comprenant des bactéries ciblant des tumeurs et un agent de chimiothérapie ou d'immunothérapie
CN117064899A (zh) * 2023-10-13 2023-11-17 暨南大学附属第一医院（广州华侨医院） 灵芝酸a在制备治疗去势抵抗性***癌的药物中的应用
CN117064899B (zh) * 2023-10-13 2024-01-23 暨南大学附属第一医院（广州华侨医院） 灵芝酸a在制备治疗去势抵抗性***癌的药物中的应用

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