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WO2005034963A1 - Utilisation de ginsenosides rh2 & rg3, et ginsenosides d'aglycone dans la prevention de cancer - Google Patents

Utilisation de ginsenosides rh2 & rg3, et ginsenosides d'aglycone dans la prevention de cancer Download PDF

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WO2005034963A1
WO2005034963A1 PCT/CA2004/001824 CA2004001824W WO2005034963A1 WO 2005034963 A1 WO2005034963 A1 WO 2005034963A1 CA 2004001824 W CA2004001824 W CA 2004001824W WO 2005034963 A1 WO2005034963 A1 WO 2005034963A1
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pharmaceutical composition
ginsenosides
aglycon
combination
administered
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Winter Huang
William Jia
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Panagin Pharmaceuticals Inc
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    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Ginsenosides Rh2 & g3, and Aglycon Ginsenosides for the Prevention of Cancer
  • the present invention is directed to ginsenosides Rh2 and Rg3, as well as aglycon ginsenosides including aglycon protopanaxadiol (aPPD) and aglycon protopanaxatriol (aPPT), or any combinations of the above for the prevention of cancers. More specifically, the present invention relates to the use of ginsenosides Rh2 and Rg3, aglycon ginsenosides including aPPD and aPPT, or any combinations of the above to reduce the production of carcinogens in the body by inhibiting certain members of the cytochrome P450 superfamily.
  • a carcinogen is a substance that causes cancer, such as aflatoxin Bl, PAHs, NNK, and 6- aminochrysene. (10th Report on Carcinogens, http://ehp.niehs.nih.gov/roc/toclO.htmt)
  • Af ⁇ atoxins are toxic and carcinogenic.
  • Aflatoxin Bl is one of the most toxic compounds known to cause cancer. It is formed commonly in crop plant materials held at relatively high moisture and temperature for long periods. At lower levels and following prolonged exposure in humans, aflatoxins can cause liver cancer. Toxicosis only takes place after consumption of the contaminated plant materials. Animals tend to avoid contaminated feed, but as Bl is so highly toxic, even large animals can be killed by small, almost undetectable quantities.
  • PAHs Polycyclic aromatic hydrocarbons
  • PAHs are a group of over 100 different chemicals that are formed during the incomplete burning of coal, oil and gas, garbage, or other organic substances like tobacco or charbroiled meat.
  • PAHs are usually found as a mixture containing two or more of these compounds, such as soot.
  • PAHs can cause harmful effects on the skin and in body fluids, and can affect the body's ability to fight disease after both short- and long- term exposure.
  • DHHS The Department of Health and Human Services of USA
  • PAHs may reasonably be expected to be carcinogens.
  • Some people who have breathed or touched mixtures of PA-Hs and other chemicals for long periods of time have developed cancer.
  • Some PAHs have caused cancer in laboratory animals when they breathed air containing PAHs (lung cancer), ingested PAHs in food (stomach cancer), or had PAHs applied to their skin (skin cancer).
  • NNK 4-(Methylnitrosamino)- 1 -(3 -pyridyl)- 1 -butanone
  • NNK was tested for carcinogenicity in several studies by subcutaneous injection in rats and hamsters and by intraperitoneal injection in mice. In rats, it induced carcinomas of the nasal cavity, lung and liver, with a clear dose-response relationship. In hamsters, it induced benign and malignant tumours of the nasal cavity, trachea and lung, even after only a single administration. In mice, TSfNK and its metabolites 4-(methylnitrosamino)-l-(3-pyridyl-N- oxide)-l -butanone and 4-(methylnitrosamino)-l-(3-pyridyl)butan-l-ol induced benign and malignant tumours of the lung.
  • ⁇ K and its metabolites can cross the placental barrier in mice.
  • ⁇ K can be metabolically activated by mouse foetal tissues.
  • Administration of ⁇ K to rats results in abnormal D A methylation in the liver and the lungs.
  • ⁇ K is mutagenic to Salmonella typhimurium in the presence of an exogenous metabolic system. It induces unscheduled D ⁇ A synthesis in primary cultures of rat hepatocytes.
  • 6-aminochrysene is one of the amino-substituted PAHs proven to be potential liver and lung carcinogens. Studies have shown that 6-aminochrysene can cause D ⁇ A single strand cleavage to form a carcinogen-D ⁇ A adduct. P450 Superfamily and Activation of Carcinogens
  • Cytochrome P450s are now known to comprise an ancient superfamily of mostly microsomal and mitochondrial heme-thiolate proteins. Having been found in every major domain of living organisms, Bacteria, Archaea and Eukarya, modern cytochrome P450s are believed to originate from an ancestral gene that existed approximately three and a half billion years ago. More than 2000 identified cytochrome P450 genomic and cDNA sequences have been divided into a total of 265 different families. Multiple cytochrome P450 genes can be expressed simultaneously and the number of genes per species is highly variable with a tendency for higher eukaryotes to possess large numbers of paralogously-related sequences.
  • yeasts have up to three cytochrome P450 genes while Caenorhabditis elegans has 80 cytochrome P450 genes (6 of which appear to be pseudogenes).
  • Drosophila melanogaster has 90 cytochrome P450 genes, 6 of which appear to be pseudogenes, and Homo sapiens have 75 cytochrome P450 genes, including 19 predicted pseudogenes. It is among plants, however, that the multiplicity of the cytochrome P450 gene family is most evident.
  • cytochrome P450 genes including 52 predicted pseudogenes
  • a record 273 cytochrome P450 genes including 26 predicted pseudogenes
  • the cytochrome P450 superfamily is a group of enzymes that are responsible for metabolizing many endogenous and exogenous substances.
  • Prokaryotic cytochror ⁇ e P450s participate in the biosynthesis of antiboiotics.
  • Fungal cytochrome P450s are required to synthesize ergosterol and facilitate phatogenesis by detoxifying the chemical defenses of target host cells.
  • cytochrome P450s serve a wide range of functions including phytohormone, petal pigment and phytoalexin biosynthesis.
  • arthropods cytochrome P450s play important roles in metabolic resistance to pesticides and in development and reproduction. Cytochrome P450s are key players in mammalian drug metabolism, steroidogenesis, the metabolism of fatty acids and the conversion of procarcinogens and promutagens to deleterious genotoxic compounds.
  • the CYP enzymes are the principle cytochrome P450 enzymes which metabolize and inactivate drugs, and in some cases activate them to active, toxic or carcinogenic products. It has been reported that certain cytochrome P450s can activate carcinogens which induce cancers. For example, carcinogens which induce bladder cancer are converted by hepatic drug metabolizing enzymes to products that are excreted and concentrated in urine. A ten-fold variation in expression was observed for cytochrome P450 CYP3 A4, with similar ranges in normal mucosa and cancer tissue. P450 CYP2C9 and CYP2C19 were intermittently expressed. Those that are expressed have a potential for contributing to carcinogenesis of bladder cancer in man. (M Romkes-Sparks, Mrna expression of individual cytochrome P450s in bladder mucosal tissue in man: potential for local production of carcinogene, Published in Cancer Detection and Prevention 1993; 17(1)).
  • Cytochrome P450s (CYP3A4, CYP2D6, CYP2C9, CYP2C19 And CYP2B6) Can Cause Precancerous Malignancies
  • cytochrome P450s including CYP3A4, CYP2D6, CYP2C9, CYP2C19 and CYP2B6, activate procarcinogens to carcinogens, such as aflatoxin Bl, PAHs, NNK, and 6- aminoehrysene, that cause carcinogenesis.
  • the CYP3 A4 enzyme is trie most important drug-metabolizing CYP in human livers. About 30-40% of the total hepatic CYP content consists of CYP3A4 (Shimada et al.1994, frnaoka et al. 1996) and it is also present in small intestines (Kolars et al. 1992). It has been estimated that about 50% of the drugs metabolized by CYPs are metabolized by CYP3A4 (Bertz & Granneman 1997).
  • the substrates for this enzyme include drugs, such as quinidine, nifedipine, diltiazem, lidocaine, lovastatin, erythromycin, cyclosporin, triazolam, and midazolam, and endogenous substances, including testosterone, progesterone, and androstenedione (Pelkonen et al. 1998, Guengerich 1999). Midazolam and erythromycin have been used as in vivo probes for CYP3A4 activity (Thummel & Wilkinson 1998). CYP3A4 also activates procarcinogens, including aflatoxin Bl (Aoyama et al.
  • the human CYP2 family is a heterogeneous group of enzymes. It contains the subfamilies CYP2A, CYP2B, CYP2C, CYP2D, CYP2E, CYP2F, and CYP2J (Nelson et al. 1996).
  • CYP2B6, CYP2D6, CYP2E1, CYP2F1, and CYP2J2 are the only functional members in their respective subfamilies, whereas the CYP2A subfamily contains two functional enzymes and CYP2C contains four functional enzymes. Unlike the CYPl family, the members of the CYP2 family do not share features of regulation. The substrate and tissue specificities of these enzymes also differ markedly.
  • CYP2B6 is a minor CYP formed in human livers, accounting for only 1-2%) of total hepatic CYP (Mimura et al. 1993, Shimada et al. 1994, hnaoka et al. 1996). Its expression appears to be regulated tissue-specifically, since in the lungs and kidneys it is expressed as a splicing variant (Czerwinski et al. 1994, Nelson et al. 1996, Gervot et al. 1999). This splicing variant was previously called CYP2B7.
  • the substrates for CYP2B6 include 6- aminochrysene (Mimura et al. 1993), methoxychlor (Dehal & Kupfer 1994), NNK (Code et al. 1997), and cyclophosphamide (Chang et al. 1993).
  • the human CYP2C subfamily contains four highly homologous genes: 2C8, 2C9, 2C18 and 2C19, which are located in a cluster on chromosome 10 (Gray et al. 1995, Nelson et al. 1996).
  • CYP enzymes are the principle enzymes which metabolize and inactivate drugs, and in some cases activate them to active, toxic or carcinogenic products.
  • Polymorphisms in CYP2C19 affect the efficacy of the common anti-ulcer agent omeprazole, one of the ten most prescribed drugs worldwide. Individuals carrying the wild-type allele have lower blood levels which results in lower cure rates. Presence of the allege is considered a risk factor for gastric cancer. (Joyce A. Goldstein, University of Texas Soiled Medical School, Pharmacology, 1968. http://dir.niehs.nih.gov/dirlpc/human.htm.) CYP2C9 is the major CYP2C in human liver.
  • drugs such as the anticonvulsant phenytoin, the common anticoagulant warfarin, antidiabetic agents such as glipizide and tolbutamide, and nonsteroidal anti-inflammatory drugs such as celecoxib, rofecoxib, and ibuprofen.
  • drugs such as the anticonvulsant phenytoin, the common anticoagulant warfarin, antidiabetic agents such as glipizide and tolbutamide, and nonsteroidal anti-inflammatory drugs such as celecoxib, rofecoxib, and ibuprofen.
  • Several drug-metabolizing enzymes such as CYP2D6, CYP2C19, CYP2C9, CYP2A6, CYPl A2, CYP1B1, CYP2A6, glutathione S-transferase Ml (GSTM1), N-acetyl transferase 2 (NAT2) are involved in the metabolism of many drugs and metabolic activation of pro-car
  • the CYP2D subfamily has one gene and four pseudogenes (Nelson et al. 1996).
  • the CYP2D6 polymorphism was the first defect in drug metabolism to be specifically associated with altered expression of a CYP enzyme (Gonzalez et al. 1988).
  • the CYP2D6 poor metabolizer (PM) phenotype is detected in about 6% of Caucasians (Ingelman-Sundberg et al. 1999), and it has profound effects on the metabolism of several commonly used pharmaceuticals, including several tricyclic antidepressants, haloperidol, metoprolol, propranolol, codeine, and dextromethorphan (Pelkonen et al. 1998).
  • CYP2D6 polymorphism
  • CYP2D6 might affect the risk of lung cancer through modulating smoking behavior, since CYP2D6 might be involved in the signal transduction of the dopaminergic pathway in brain (Saarikoski et al. 2000).
  • CYP2D6 constitutes about 2% of total hepatic CYP (Shimada et al. 1994, Imaoka et al. 1996), and the protein is also expressed in the duodenum and brain (Pelkonen & Raunio 1997).
  • ginsenosides are the main active components of ginseng, and that they have various medicinal effects.
  • the use of ginseng has various pharmacological benefits.
  • ginsenosides are named according to the orders of their Rf values on thin- layer chromatograms, such as Ra, Rbl, Rb2, Re, Rd, Re, and Rf. Based on their aglycons, i.e. the skeletons of their molecules, ginsenosides are classified into three types: 1) Dammarane, 2) Ocotillol, and 3) Oleanane.
  • the tetracyclic-terpene-structured dammarane type can be further divided into two subtypes: protopanaxatriol and protopanaxadiol (Chan, But, 2000; Chen, Zhang, 1990; Cheng, Su, 1987; Corthout, Naessens, 1999; Cui, Garle, 1996; Cui, Song, 2000; Elkin, Makhankov, 1993 ; Kaku and Kawashima, 1980; Karikura, Miyase, 1990; Liu, Luo, 1989; Ong and Yong, 2000;Oura, Hiai, 1975; Shaol984; Takino, Odani, 1982; Wang, Sakuma, 1999; Yang and Xu, 1987; Yip, Lau, 1985; Yoshikawa, Murakami, 1998; Zhang, Chen, 1989; Zhao and Yuan, 1993).
  • the structures of Rhl, Rh2, and Rg3, the structural types and classification of common ginsenosides, are as follows:
  • Rh2 could induce differentiation in B16 melanoma and F9 teratocarcinoma stem cells (Lee, Lee, 1996; Odashima, Ohta, 1985; Xia and Han, 1996). Rh2 can inhibit the proliferation of r urine melanoma, human MCF-7 breast cancer cells, ovarian cancer cells, and liver cancer SKL-HEP-1 cells in vitro (Kikuchi, et al. 1991 DLee, et al. 1996DOta, Maeda, Odashima, Nino iya, and Tatsuka, 1997DOh, et al. 1999DPopovich and Kitts, 2002).
  • Rh2 may involve expression of ⁇ 27kipl (Lee, et al. 1996), p21WAFl/CIPl (Oh, et al. 1999), and/or suppression of cyclin-dependent kinase- 2 (Cdk2) (Ota, Maeda, Odashima, Ninomiya, and Tatsuka, 1997).
  • Ginsenoside Rg3 is very similar to Rh2 in its chemical structure (one more glucose at C-3 than Rh2), and can inhibit invasion by rat ascites hepatoma, mouse melanoma, human small- cell lung carcinoma, and human pancreatic adenocarcinoma cells in vitro (Shinkai, Akedo, Mukai, Imamura, Isoai, Kobayashi, and Kitagawa, 1996). In vivo studies have found that Rg3 can inhibit lung metastasis by highly metastatic melanoma and colon carcinoma in mice (Iishi, Tatsuta, Baba, Uehara, Nakaizumi, Shinkai, Akedo, Funai, Ishiguro, and Kitagawa, 1997). However, because of its multi -glucose chemical structure, Rg3's cytotoxicity is much lower than that of Rh2 and sapogenins.
  • aglycon of protopanaxadiol ginsenosides has been reported to have the strong inhibitory effects on B 16 melanoma cell proliferation (Ota, Maeda, Odashima, 1991)DTHP-1 leukemia cells (Popovich and Kitts2002), and multi-drug resistant P388/ACM leukemia cells (Hasegawa, Sung, Matsumiya, Uchiyama, Inouye, Kasai, and Yamasaki, 1995).
  • the aglycon of protopanaxatriol ginsenosides which has no glucose on its chemical structure, has also been reported to have the similar anticancer effects as PPD (Shibata, 2001 DPopovich and
  • the only structural difference between aPPD and aPPT is at C-6, with an "-H” for aPPD, but an "-OH” for aPPT.
  • the two known sapogenins, aglycon protopanaxadiol and aglycon protopanaxadiol have further been demonstrated to be effective in chemosensitizing multi- drug resistant (MDR) cancer cells when used with other chemotherapy drugs in vitro (U.S. Patent Application No. 09/957,082).
  • Ginsenoside Rh2, Rg3, aPPD and aPPT are found in the plants of the ginseng family in extremely scarce amounts.
  • the content of Rh2 is only 0.001% (lg of Rh2 in every 100kg of red ginseng), and the contents of 20(S)-Rg3 and 20(R)- Rg3 in red ginseng is 0.015% and 0.014% respectively (Shibata, 2001).
  • PPD Protopanaxadiol
  • PPT Protopanaxatriol
  • Aglycon Ginsenosides Aglycon Ginsenosides
  • Aglycon Protopanaxadiol aPPD
  • Aglycon Protopanaxatriol aPPT
  • PPD/ PPT is broadly used to indicate a group of compounds with the following chemical structures, wherein the j and 2 have different components: (CHEMTECH 1998, 28(A), 26-32.)
  • Rg 3 is a mixture of S and R configurations.
  • Rh 2 , Rs 2 , and NG-R 4 are found only in red ginseng.
  • Rg 2 and Rhi All compounds have a 20S configuration except Rg 2 and Rhi.
  • aglycon ginsenosides is used to describe a group of ginseng sapogenins, which are totally free of glucose in their chemical structures, including, but not limited to, compounds such as aPPD, aPPT, PAM-120, PBM-110, PBM-100.
  • aPPD and "aPPT” are used to describe the following two specific aglycon sapogenins:
  • hydroxyl group of aPPT above in position 6 may be R or S epimers.
  • PAM-120, PBM-110, and PBM-100 are used to describe the following specific aglycon sapogenins:
  • the term "Combination” is used to describe any combinations of a group of two or more ginseng saponins or sapogenins, including, but not limited to, compounds such as ginsenoside Rh2, Rg3, aPPD, aPPT, PAM-120, PBM-110, and PBM-100.
  • Careseng 2131 which is a combination of ginsenoside Rh2 (1%-10%), aPPD(20%-50%), aPPT(15%-45%) and small portion of other ginsenosides( ⁇ 5%), is used.
  • Cytochrome P-450 metabolism can be affected by traditional Chinese medicines (includingGinseng Dao, Panax Ginseng Extractum, and Ginseng-Royal Jelly) in vitro
  • An object of the present invention is to provide a use of Rh2, Rg3, aglycon ginsenosides including aPPD and aPPT, and any combinations of the above for reducing the production of carcinogens in the body by inhibiting certain cytochrome P450s.
  • a method of preventing cancers in humans comprising administering to humans an effective amount of Rh2, Rg3, aglycon ginsenosides including aPPD and aPPT, or any combinations of these compounds .
  • a pharmaceutical composition comprising Rh2, Rg3, aglycon ginsenosides including aPPD and aPPT, or any combinations of these compounds useful for preventing a human subject from developing cancer.
  • a non-pharmaceutical composition comprising Rh2, Rg3, aglycon ginsenosides including aPPD and aPPT, or any combinations of these compounds useful for preventing a human subject from developing cancer.
  • kits comprising one or more pharmaceutical compositions comprising Rh2, Rg3, aglycon ginsenosides including aPPD and aPPT, or any combinations of these compounds, useful for preventing a human subject from developing cancer.
  • FIG. 1 is a graphical representation of the inhibitory effects of Rh2, Rg3, aglycon ginsenosides aPPD and aPPT, and one combination of the above on the human cytochrome P450 CYP3A4.
  • FIG. 2 provides a graphical representation of the inhibitory effects of Rh2, aglycon ginsenosides including aPPD and aPPT, and one combination of the above on the human cytochrome P450 CYP2D6;
  • FIG. 3 provides a graphical representation of the inhibitory effects of Rh2, aglycon ginsenosides including aPPD and aPPT, and one combination of the above on the human cytochrome P450 CYP2C9;
  • FIG. 4 provides a graphical representation of the inhibitory effects of Rh2, aglycon ginsenosides including aPPD and aPPT, and one combination of the above on the human cytochrome P450 CYP2C19;
  • FIG. 5 provides a graphical representation of the inhibitory effects of Rh2, aglycon ginsenosides including aPPD and aPPT, and one combination of the above on the human cytochrome P450 CYP2B6.
  • cancer prevention is defined as the following: preventing any type of cancer or precancer malignancy from developing, or reducing the chances of any type of cancer or precancer malignancy from developing.
  • Rh2, Rg3, aglycon ginsenosides including aPPD and aPPT, and any combinations of these compounds can inhibit certain members of the cytochrome P450 superfamily. More specifically, Rh2, Rg3, aglycon ginsenosides aPPD and aPPT, and combinations of these ginsenosides, have strong dose-dependent inhibitory effects on the following P450 enzymes: CYP3A4, CYP2D6, CYP2C9, CYP2C19 and CYP2B6.
  • P450 isoenzymes are known to produce carcinogens. Therefore, inhibition of these enzymes reduces the production of carcinogens in the human body. The end result is a decrease in carcinogenesis. Therefore, when P450s are inhibited, they prevent or reduce the chances of developing cancer.
  • the invention pertains to a method of preventing cancer in humans or other animals.
  • the method involves the administration of an effective amount Rh2, Rg3, aglycon ginsenosides, including aPPD, aPPT, P AM- 120, PBM- 100, and PBM- 110, or any combination of these compounds, to inhibit the activity of cytochrome P450 enzymes, including CYP3A4, CYP2D6, CYP2C9, CYP2C19, and CYP2B6.
  • the method can be administered with compounds Rh2, Rg3, and aglycon ginsenosides including aPPD and aPPT, in a non-purified form, in which the purity of each compound is lower than 50%.
  • the method can also be administered with compounds Rh2, Rg3, and aglycon ginsenosides including aPPD and aPPT, in a purified form in which the purity of each compound is above 50%.
  • the concentration of each compound in the combination formula may range between 0.2%> and 99% of each component in the formula.
  • the method can be administered to a healthy person, or a person who belongs to one of following groups of people who are at high-risk of developing cancer: smokers, ex-smokers, workers in certain industries such as mining, persons with a family history of cancer, persons who have had diseases that are known to cause cancer, such as hepatitis and AIDS, persons who are exposed to radiation and certain chemicals that are known to cause cancer.
  • Rh2, Rg3, aglycon ginsenosides including aPPD and aPPT, or any combinations of the above can be used as cancer prevention agents administered to a cancer survivor whose cancer is cured to prevent cancer from recurring.
  • the method can be used to prevent cancers such as lung, breast, prostate, colon, rectal, pancreatic, bladder, kidney, uterine, mouth, stomach, ovarian, brain, thyroid, cervical, esophageal, laryngeal, and testical cancers, as well as non-Hodgkin's lymphoma, melanoma, leukemia, multiple myeloma, and Hodgkin' s Disease.
  • cancers such as lung, breast, prostate, colon, rectal, pancreatic, bladder, kidney, uterine, mouth, stomach, ovarian, brain, thyroid, cervical, esophageal, laryngeal, and testical cancers, as well as non-Hodgkin's lymphoma, melanoma, leukemia, multiple myeloma, and Hodgkin' s Disease.
  • Rh2, Rg3, aglycon ginsenosides including aPPD and aPPT, or any combinations of the above can be administered as pharmaceutical or non-pharmaceutical compositions.
  • compositions The isolation and purification of Rh2, Rg3, aglycon ginsenosides including aPPD and aPPT, or any combinations of the above from natural sources has been described in the art.
  • the pharmaceutically active compound may be administered as pharmaceutical compositions with an appropriate pharmaceutically acceptable carrier, diluent, recipient or vehicle.
  • the pharmaceutical compositions may also be formulated to contain Rh2, Rg3, aglycon ginsenosides including aPPD and aPPT, or any combinations of the above compounds for administration to a human subject.
  • compositions of the present invention maybe administered orally, topically, by injection, by inhalation or spray, or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • parenteral as used herein include subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
  • compositions may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions and may contain one or more agents selected from the group of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets contain the active ingredient in admixture with suitable non-toxic pharmaceutically acceptable excipients including, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as corn starch, or alginic acid; binding agents, such as starch, gelatine or acacia, and lubricating agents, such as magnesium stearate, stearic acid or talc.
  • suitable non-toxic pharmaceutically acceptable excipients including, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as corn starch, or alginic acid; binding agents, such as starch, gelatine or acacia, and lubricating agents, such as magnesium stearate, stearic acid or talc.
  • the tablets can be uncoated,
  • compositions for oral use may also be presented as hard gelatine capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatine capsules wherein the active ingredient is mixed with water or an oil medium such as peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • an oil medium such as peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions contain the active compound in admixture with suitable excipients including, for example, suspending agents, such as sodium carboxymethylcellulose, methyl cellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example, polyoxyethyene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, hepta-decaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol for example, polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example, polyethylene sorbitan monooleate.
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl »-hydroxy-benzoate, one or more colouring agents, one or more flavouring agents or one or more sweetening agents, such as sucrose or saccharin.
  • preservatives for example ethyl, or n-propyl »-hydroxy-benzoate
  • colouring agents for example ethyl, or n-propyl »-hydroxy-benzoate
  • flavouring agents for example sucrose or saccharin.
  • sweetening agents such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example, beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and/or flavouring agents may be added to provide palatable oral preparations. These compositions can be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active compound in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent, suspending agent and one or more preservatives are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavouring and colouring agents, may also be present.
  • compositions of the invention may also be in the form of oil-in- water emulsions.
  • the oil phase maybe a vegetable oil, for example, olive oil or arachis oil, or a mineral oil, for example, liquid paraffin, or it may be a mixture of these oils.
  • Suitable emulsifying agents may be naturally-occurring gums, for example, gum acacia or gum tragacanth; naturally-occurring phosphatides, for example, soy bean, lecithin; or esters or partial esters derived from fatty acids and hexitol, anhydrides, for example, sorbitan monoleate, and condensation products of the said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monoleate.
  • the emulsions may also contain sweetening and flavouring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, and/or flavouring and colouring agents.
  • sweetening agents for example, glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, and/or flavouring and colouring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to known art using suitable dispersing or wetting agents and suspending agents such as those mentioned above.
  • the sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example, as a solution in 1,3- butanediol.
  • Acceptable vehicles and solvents that may be employed include, but are not limited to, water, Ringer's solution, lactated Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils which are conventionally employed as a solvent or suspending medium
  • a variety of bland fixed oils including, for example, synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • compositions and methods of preparing pharmaceutical compositions are known in the art and are described, for example, in “Remington: The Science and Practice of Pharmacy,” Gennaro, A., Lippincott, Williams & Wilkins, Philidelphia, PA (2000) (formerly “Remingtons Pharmaceutical Sciences '1 ).
  • Non-Pharmaceutical Compositions are known in the art and are described, for example, in “Remington: The Science and Practice of Pharmacy,” Gennaro, A., Lippincott, Williams & Wilkins, Philidelphia, PA (2000) (formerly “Remingtons Pharmaceutical Sciences '1 ).
  • An important aspect of the invention provides for ginsenoside Rh2, Rg3, aglycon ginsenosides including aPPD and aPPT, or any combinations of the above to be administered as a non-pharmaceutical composition in an appropriate pharmacologically acceptable medium such as a buffer, a solvent, a diluent, an inert carrier, an oil, a creme, or an edible material.
  • the non-pharmaceutical formulation may be in the form of, for example, a nutraceutical composition, a food, a health food, a natural health product, a functional food, a nutritional supplement, a dietary supplement, an herbal supplement, an herb, an alternative medicine, or a naturopathic product.
  • the composition of the present invention is provided as a non-pharmaceutical formulation in a pharmacologically acceptable medium.
  • the non-pharmaceutical formulations disclosed herein may typically be orally administrable in the form of a tablet, a powder, a suspension, an emulsion, a capsule, a granule, a troche, a lozenge, a pill, a liquid, a spirit, a syrup, an elixir, and a drink.
  • the nonpharmaceutical composition may also be administered topically in the form of a drop, a paste, an ointment, a liquid, a powder, a plaster, a suppository, an aerosol, a liniment, a lotion, an enema and an emulsion.
  • the pharmaceutical and non-pharmaceutical composition may comprise am effective amount of Rh2, Rg3, aglycon ginsenosides including aPPD and aPPT, or any combinations of the above in a pharmacologically acceptable medium.
  • the active daily dose of Rh2 is 0.1 mg to 5g per day per person, or preferably, 0.5 mg to 2g per day per person;
  • the active daily dose of Rg3 is 0.1 mg to 5g per day per person, or preferably, 0.5 mg to 2g per day per person;
  • the active daily dose of aglycon ginsenoside aPPD is 0.1 mg to 5g per day per person, or preferably, 0.5 mg to 2g per day per person;
  • the active daily dose of aglycon ginsenoside aPPT is 0.1 mg to 5g per day per person, or preferably, 0.5 mg to 2g per day per person;
  • the active daily dose of composition comprising of two or more of Rh2, Rg3, and aglycon ginsenoside aPPD or aPPT is 0.1 mg to 5g per day per person, or preferably, 0.5 mg to 2g per day per person.
  • an effective amount of Rh2, Rg3, aglycon ginsenosides including aPPD and aPPT, or a combination of the above is administered to a subject in order to prevent cancer.
  • the Rh2, Rg3, aglycon ginsenosides including aPPD and aPPT, or a pharmaceutical composition comprising Rh2, Rg3, aglycon ginsenosides including aPPD and aPPT may be administered in a manner consistent with medical practice.
  • Rh2, Rg3, aglycon ginsenosides including aPPD and aPPT, or any combinations of the above to be administered will be dependent upon the size of the subject and can be readily determined by a skilled practitioner. It is to be understood, however, that the dosage and frequency of administration may be adapted to the circumstances in accordance with known practices in the art, for the prevention of cancers.
  • the present invention additionally provides pharmaceutical kits containing Rh2, Rg3, aglycon ginsenosides including aPPD and aPPT, or any combinations of the above in pharmaceutical compositions for use in the prevention of cancers.
  • Individual components of the kit could be packaged in separate containers.
  • the liquid solution can be an aqueous solution, for example a sterile aqueous solution.
  • the container means may itself be an inhalant, syringe, pipette, eye dropper, or other such like apparatus, from which the composition may be administered to a subject.
  • kits of the invention may also be provided in dried or lyophilised form and the kit can additionally contain a suitable solvent for reconstitution of the lyophilised components.
  • the kits of the invention also may comprise an instrument for assisting with the administration of the composition to a subject.
  • Such an instrument may be an inhalant, syringe, pipette, forceps., measured spoon, eyedropper or any such medically approved delivery vehicle.
  • Test methods are based on the protocols provided by the manufacturer of inhibitor screening kits of the above listed cytochrome p450s. Briefly, recombinant human P450 (SUPERSOMES ) were incubated together with their fluorescent substrates in a buffer containing NADP+, Glucose-6-Phosphate, Magnesium Chloride, Glucose-6-Phosphate Dehydrogenase and the drug substance Rh2, Rg3, aglycon ginsenosides aPPD and aPPT, and a combination of the above (Careseng 2131) at various concentrations for a given time and then the activities of the enzymes CYP3A4, CYP2D6, CYP2C9, CYP2C19 and CYP2B6 were measured at suitable excitation and emission wavelengths. In each experiment, a reaction with a known inhibitor of the tested enzyme was included as a positive control.
  • Table 3 Demonstration of inhibition ofCYP3A4, CYP2D6, CYP2C9, CYP2C19, and CYP2B6 by their known inhibitors.
  • Fig.1 is a graph of the activity of cytochrome P450 enzyme CYP3 A4 in the presence of 0 to
  • Fig. 2 is a graph of the activity of cytochrome P450 enzyme CYP2D6 in the presence of 0 to 60ug ml of Rh2, Rg3, aPPD, aPPT and Careseng 2131 (a combination of Rh2, aPPD and aPPT). The activity of CYP2D6 is inhibited in a dose dependent manner in the presence of these compounds.
  • Fig. 3 is a graph of the activity of cytochrome P450 enzyme CYP2C9 in the presence of 0 to 60ug ml of Rh2, Rg3, aPPD, aPPT, and Careseng 2131 (a combination of Rh2, aPPD and aPPT).
  • the activity of CYP2D6 is inhibited in a dose dependent manner in the presence of these compounds.
  • Fig. 4 is a graph of the activity of cytochrome P450 enzyme CYP2C19 in the presence of 0 to 60ug/ml of Rh2, Rg3 , aPPD, aPPT, and Careseng 2131 (a combination of Rh2, aPPD and aPPT).
  • the activity of CYP2C19 is inhibited in a dose dependent manner in the presence of these compounds.
  • Fig. 5 graph of the activity of cytochrome P450 enzyme CYP2B6 in the presence of 0 to 60ug ml of Rh2, Rg3, aPPD, aPPT, and Careseng2131 (a combination of Rh2, aPPD and aPPT).
  • the activity of CYP2B6 is inhibited in a dose dependent manner in the presence of these compounds.
  • AFBl a AFBl, a mycotoxin produced by Aspergillus flavus
  • Aspergillus flavus is considered to be an important factor for liver cancers in Africa and Southeast Asia. It is activated into AFBl exo-8,9- epoxide by cytochrome P450s (P450 3A4, etc). AFBl can also be activated into tumour on rat by its P450s.
  • cytochrome P450s P450 3A4, etc.
  • AFBl can also be activated into tumour on rat by its P450s.
  • Vesselinovitch et al. discovered that AFBl causes liver tumors in mice when administered to newborn animals, and this model is now well established.
  • AFBl (Sigma, USA), Ginsenoside Rh2, Rg3, aPPD, and Composition (Careseng 2131) were obtained from Pegasus Pharmaceuticals Group Inc. (Richmond, B.C. Canada). Diet was freshly prepared every week. Food and water were provided ad libitum.
  • Group 2 Rh2 group: j'jff ⁇ ⁇ k ⁇ hft-i
  • Group 3 Rg3 group:
  • Group 4 aPPD group: Z ' * /% & ⁇ " -Bi': sfffi f ⁇ ⁇ > ⁇ ⁇ • -
  • livers were grossly examined and nodules larger than 1 mm in diameter were counted as tumors. After fixation in 10% formaldehyde solution, each liver lobe will be completely cut into 2.0 mm thick slices and processed for light microscopy. Diagnosis of hepatocellular adenomas and carcinomas was made microscopically based on established diagnostic criteria (2). Hepatocellular adenomas were at most 5-10 mm in diameter and clearly demarcated. Relatively small and monotonous tumor cells proliferate, forming a thin trabecular pattern. Hepatocellular carcinomas showed a thick trabecular growth pattern with dilated sinusoids.
  • Table 2 shows the prevention effects of different ginsenosides on Aflatoxin Bl -induced tumorigenesis.
  • This example shows the preventative effects of different ginsenosides on P450s-dependent carcinogen AFBl on F344 rats.
  • P450s are known to produce carcinogens. Therefore, inhibition of these enzymes reduces the production of carcinogens in the human body. Therefore, when P450s are inhibited, they prevent or reduce the chances of developing cancer.
  • the production of carcinogens in the body is widespread and occurs in almost all of the organs, such as in skin, lung, breast, prostate, colon, rectal, pancreatic, bladder, kidney, uterine, bile duct, mouth, throat, stomach, ovarian, brain, thyroid, cervical, esophageal, laryngeal, and testicular. Therefore, many types of cancer are therefore prevented.

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Abstract

L'invention concerne une méthode de prévention de cancer chez des êtres humains ou d'autres animaux par administration de ginsenosides Rh2, Rh3, de ginsenosides d'aglycone ou de toute combinaison associée à des êtres humains ou à des animaux. Ces ginsenosides et ginsenosides d'aglycone permettent de prévenir ou de diminuer les risques de développer un cancer ou des malignités précancéreuses par inhibition des activités des enzymes p450 de cytochrome. Ladite invention a également pour objet des compositions pharmaceutiques et non pharmaceutiques dans la prévention de cancer chez des êtres humains ou d'autres animaux.
PCT/CA2004/001824 2003-10-15 2004-10-15 Utilisation de ginsenosides rh2 & rg3, et ginsenosides d'aglycone dans la prevention de cancer Ceased WO2005034963A1 (fr)

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WO2008010668A1 (fr) * 2006-07-18 2008-01-24 Sk Chemicals Co., Ltd. 20(s -ginsénoside rg3 en tant que composition anti-angiogène
CN101849954A (zh) * 2010-06-07 2010-10-06 上海市计划生育科学研究所 化合物20(S)-人参皂甙Rh2在制备治疗妇科生殖系统良性增生性疾病药物中的应用
RU2432164C2 (ru) * 2006-05-22 2011-10-27 Далянь Фушэн Нэчурал Медсин Дивелопмент Ко., Лтд ВОДНЫЙ РАСТВОР ФАРМАЦЕВТИЧЕСКОЙ КОМПОЗИЦИИ 20(R)-ГИНСЕНОЗИДА Rg3 И СПОСОБ ЕГО ПРИГОТОВЛЕНИЯ
US20130122122A1 (en) * 2010-05-14 2013-05-16 Greencross Herb & Pharmaceutical Co., Ltd. Method for preparing novel processed ginseng or an extract thereof, the usually minute ginsenoside content of which is increased
CN105287611A (zh) * 2014-06-27 2016-02-03 江苏命码生物科技有限公司 人参皂苷Rh2在抑制Treg细胞中的应用
US10709749B2 (en) 2013-08-30 2020-07-14 Green Cross Wellbeing Corporation Composition for preventing and treating cancer-related fatigue, containing processed ginseng powder or processed ginseng extract having increased ginsenoside constituent
CN111615393A (zh) * 2018-04-17 2020-09-01 理筱龙 人参皂苷m1用于制造供治疗口腔癌的药物的用途
CN115006414A (zh) * 2020-07-01 2022-09-06 香港浸会大学深圳研究院 人参皂苷Rg3的新用途
WO2023090888A1 (fr) * 2021-11-19 2023-05-25 케이블루바이오 주식회사 Composition pour la prévention ou le traitement du myélome multiple comprenant un nouveau composé de triterpène tétracyclique en tant que principe actif
WO2024223797A1 (fr) 2023-04-28 2024-10-31 Institut National de la Santé et de la Recherche Médicale Utilisation d'inhibiteurs de cyp3a4 pour le traitement d'infections par le virus de l'hépatite d (vhd)

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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2432164C2 (ru) * 2006-05-22 2011-10-27 Далянь Фушэн Нэчурал Медсин Дивелопмент Ко., Лтд ВОДНЫЙ РАСТВОР ФАРМАЦЕВТИЧЕСКОЙ КОМПОЗИЦИИ 20(R)-ГИНСЕНОЗИДА Rg3 И СПОСОБ ЕГО ПРИГОТОВЛЕНИЯ
WO2008010668A1 (fr) * 2006-07-18 2008-01-24 Sk Chemicals Co., Ltd. 20(s -ginsénoside rg3 en tant que composition anti-angiogène
US9512453B2 (en) 2010-05-14 2016-12-06 Green Cross Wellbeing Corporation Method for preparing novel processed ginseng or an extract thereof, the usually minute ginsenoside content of which is increased
US20130122122A1 (en) * 2010-05-14 2013-05-16 Greencross Herb & Pharmaceutical Co., Ltd. Method for preparing novel processed ginseng or an extract thereof, the usually minute ginsenoside content of which is increased
EP2570132A4 (fr) * 2010-05-14 2013-12-18 Greencross Herb & Pharmaceutical Co Ltd Procédé de préparation de nouveau ginseng traité ou d'un extrait de celui-ci, dont la teneur en ginsénoside, généralement infime, est accrue
CN101849954A (zh) * 2010-06-07 2010-10-06 上海市计划生育科学研究所 化合物20(S)-人参皂甙Rh2在制备治疗妇科生殖系统良性增生性疾病药物中的应用
US10709749B2 (en) 2013-08-30 2020-07-14 Green Cross Wellbeing Corporation Composition for preventing and treating cancer-related fatigue, containing processed ginseng powder or processed ginseng extract having increased ginsenoside constituent
US11464821B2 (en) 2013-08-30 2022-10-11 Green Cross Wellbeing Corporation Composition for reducing cancer cachexia or weight loss caused by anticancer drug therapy or radiation therapy comprising ginseng extract having increased ginsenoside Rg3 and Rh2
CN105287611A (zh) * 2014-06-27 2016-02-03 江苏命码生物科技有限公司 人参皂苷Rh2在抑制Treg细胞中的应用
CN111615393A (zh) * 2018-04-17 2020-09-01 理筱龙 人参皂苷m1用于制造供治疗口腔癌的药物的用途
CN111615393B (zh) * 2018-04-17 2023-10-10 理筱龙 人参皂苷m1用于制造供治疗口腔癌的药物的用途
CN115006414A (zh) * 2020-07-01 2022-09-06 香港浸会大学深圳研究院 人参皂苷Rg3的新用途
CN115006414B (zh) * 2020-07-01 2024-04-09 香港浸会大学深圳研究院 人参皂苷Rg3的新用途
WO2023090888A1 (fr) * 2021-11-19 2023-05-25 케이블루바이오 주식회사 Composition pour la prévention ou le traitement du myélome multiple comprenant un nouveau composé de triterpène tétracyclique en tant que principe actif
WO2024223797A1 (fr) 2023-04-28 2024-10-31 Institut National de la Santé et de la Recherche Médicale Utilisation d'inhibiteurs de cyp3a4 pour le traitement d'infections par le virus de l'hépatite d (vhd)

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