WO1995003809A2 - Inhibiteurs de tumeurs - Google Patents

Inhibiteurs de tumeurs Download PDF

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Publication number
WO1995003809A2
WO1995003809A2 PCT/GB1994/001676 GB9401676W WO9503809A2 WO 1995003809 A2 WO1995003809 A2 WO 1995003809A2 GB 9401676 W GB9401676 W GB 9401676W WO 9503809 A2 WO9503809 A2 WO 9503809A2
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WO
WIPO (PCT)
Prior art keywords
glucokinase
tumour
cells
cell
inhibitor
Prior art date
Application number
PCT/GB1994/001676
Other languages
English (en)
Other versions
WO1995003809A3 (fr
Inventor
Mary Board
Eric Arthur Newsholme
Original Assignee
Isis Innovation Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Isis Innovation Limited filed Critical Isis Innovation Limited
Priority to AU72692/94A priority Critical patent/AU7269294A/en
Publication of WO1995003809A2 publication Critical patent/WO1995003809A2/fr
Publication of WO1995003809A3 publication Critical patent/WO1995003809A3/fr

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Classifications

    • 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
    • A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H7/00—Compounds containing non-saccharide radicals linked to saccharide radicals by a carbon-to-carbon bond
    • C07H7/02—Acyclic radicals

Definitions

  • Indications are that the in vivo activity of this enzyme may approach its maximal in vitro activity (Board, 1990 (b)). Moreover, given the high intracellular concentrations of glucose in some tumour cells, hexokinase may approach saturation with its pathway substrate (Board, 1990 (b)). In this case, hexokinase may be the flux-generating step for glycolysis in the tumour cell. This would be an unusual situation, since for tissues such as muscle, it is considered that the step of glucose import into the cell constitutes the flux-generating step (Newsholme and Board, 1991).
  • hexokinase in tumour cells raises many interesting possibilities. Factors which act on the enzyme in such a way as to affect its in vivo activity will alter the rate of flux through glycolysis and this process will be independent of the intracellular glucose concentration.
  • hexokinase IV glucokinase
  • the invention provides a method of inhibiting the growth of tumour cells comprising contacting the cells with an inhibitor of glucokinase.
  • the invention also provides the use of an inhibitor of glucokinase for inhibiting the growth of tumour cells.
  • the inhibitor of glucokinase may be any compound which suppresses or inhibits the activity of the glucokinase enzyme, either directly or indirectly.
  • the inhibitor is preferably otherwise substantially non-toxic.
  • Compounds which inhibit glucokinase directly include certain sugars and sugar analogues, such as some substituted or unsubstituted hexoses and heptoses.
  • Glucokinase inhibitors include the following compounds and their analogues and derivatives:
  • D-Mannoheptulose D-mannoketoheptose
  • mannoheptose both of which are commercially available.
  • Indirect inhibitors of glucokinase will include for example compounds which reduce or block transcription of the glucokinase gene or translation of the mRNA, such as oligonucleotide sequences or
  • oligonucleotide-analogue sequences which are capable of hybridising to part or all of the DNA or RNA sequences which encode glucokinase. It is expected that abnormal derepression of the glucokinase gene in tumour cells is causing the abnormal production of the glucokinase enzyme. Thus, interruption of transcription- or translation-related events is one way to inhibit glucokinase in an indirect fashion.
  • glucokinase gene are known and published. (Andreone et al., 1989; Magnuson et al., 1989).
  • a further type of glucokinase inhibitor uses the "magic bullet” approach and involves antibodies directed to eg. glucokinase or glucokinase mRNA. Such antibodies can be raised by known methods, including the development of hybridomas which secrete monoclonal antibodies of the desired specificity.
  • the invention also provides novel compounds which inhibit glucokinase, such as compounds (3), (4) and (7) in table 7 below.
  • novel compounds which inhibit glucokinase, such as compounds (3), (4) and (7) in table 7 below.
  • the compounds will be suitable for inhibiting the growth of tumour cells.
  • the compounds may be useful in therapy, particularly for treatment of tumours.
  • the invention also provides compositions comprising such compounds, for inhibiting the growth of tumour cells.
  • Inhibitors having I values, (I 50 being the concentration required to inhibit enzyme activity by 50%) of between ⁇ 1 ⁇ M and 250mM, are expected to be effective in tumour inhibition. Inhibitors having an
  • I 50 in the range 100 ⁇ M to 35mM will be most useful.
  • a further aspect of the invention is the treatment of patients with tumours.
  • the invention provides a method of treatment of a tumour in a patient comprising administering an effective amount of a glucokinase inhibitor to the patient; or alternatively, the use of a glucokinase inhibitor for the treatment of a tumour in a patient.
  • Administration may be by any route, such as oral, intravenous, intraperitoneal or direct injection into the tumour. Most probably, compounds will be given orally or by intravenous infusion.
  • the invention also provides the use of a glucokinase inhibitor in the manufacture of a
  • a biopsy sample showing glucokinase activity would indicate the likelihood that this mode of treatment would be successful.
  • a pharmaceutical formulation comprising a glucokinase inhibitor and a pharmaceutically acceptable carrier.
  • a scheme envisaged for treatment of patients involves administration of mannoheptulose, which is thought to be free of toxic side-effects and is a naturally-occurring compound, or of other glucokinase inhibitors, to patients between bouts of radiotherapy or chemotherapy.
  • This scheme including comparison with a control group receiving a placebo, would form the basis of clinical trials.
  • the mannoheptulose (or other glucokinase inhibitor) and control groups will be matched for age, state of progression of the disease and state of health discounting the cancer.
  • An upper limit of dosage of mannoheptulose would be in the region of 200mg/kg. This reduces to an approximate equation for other inhibitors of
  • a combination of two or more glucose inhibitors may be used.
  • the invention provides a method of diagnosing a tumour comprising detecting the presence of glucokinase activity, or of glucokinase protein or messenger RNA (mRNA) , or expression of the glucokinase gene, in a sample suspected of containing malignant or premalignant cells.
  • the invention also provides compounds which bind specifically to glucokinase or glucokinase mRNA for use in the diagnosis of tumours.
  • Diagnostic tests may require a small biopsy sample, or in the case of non-solid tumours such as leukemia, a blood sample could be used. Examples of possible diagnostic tests are as follows:
  • Probing for glucokinase protein or messenger RNA with a radiolabelled probe in a population of extraheptatic and extapancreatic cells would show the presence of glucokinase in tumorigenic cells.
  • the gene sequence of glucokinase is known and 45% of it has been published. This is a technique of great sensitivity and would be expected to give positive results for a population of cells containing only a small proportion of tumorigenic cells. Since the suppressed cells of the present study (see Examples) also show glucokinase activity, it is expected that pre-malignant cells would also test positive enabling preventive treatment to be administered before the tumour cells begin to proliferate.
  • mannoheptulose or another inhibitor of glucokinase is another inhibitor of glucokinase.
  • Malignant or pre-malignant cells will have their rates of growth inhibited under these conditions, whereas normal cells will not.
  • Diagnosis may involve using a probe as noted above, labelled with a suitable label.
  • labelled antibodies in particular monoclonal antibodies raised against the glucokinase nRNA or the glucokinase
  • molecule itself may provide suitable compounds for use in diagnosis.
  • the magnitude of glucokinase activity may relate to malignancy of the tumour and if so, will be useful in prognosis.
  • glucokinase inhibitors demonstrated in the Examples act on glucokinase by an unknown
  • glucokinase inhibitors which may be based on hexose or heptose sugars or which may be entirely different types of compound.
  • Glucokinase has a much higher specificity for glucose than the other hexokinase enzymes. Hexakinases I, II and III are capable of phosphorylating many different sugars, but glucokinase is not. Glucose has a high Km (which describes how high the concentration of the substrate needs to be before an enzyme will work), of about 10mM for glucose. This is useful for liver cells as it allows high levels of glucose to accumulate. Other hexakinases are low Km enzymes, which work in the presence of a much lower concentration of substrate.
  • H.Ep 2 epithelial cell from primary carcinoma of the larynx (morphologically indistinguishable from the HeLa cell) (Moore, 1955).
  • ESH TR1-2 and ESH p6 hybrid matched pair resulting from somatic cell hybridisation of a HeLa cell derivative, D98, and a human
  • keratinocyte (Peehl et al., 1981).
  • RVH 421 melanoma cell-line (McCormick et al., 1983).
  • HT29 carcinoma of the colon (epithelial) (Marshall, 1977).
  • RT112 carcinoma of the urinary epithelium (Marshall, 1977).
  • T24/83 bladder carcinoma (Bubenik et al., 1973).
  • MRC 5 diploid fibroblast from foetal lung of 14 weeks gestation. MRC 5 persists for 48 passages before the onset of senescence (Jacobs, 1970).
  • Hs578T breast carcinoma cell line (Hackett et al).
  • ZR-75-1 and T47D breast carcinoma cell lines (Engel and Young, 1978).
  • MCF-7 breast carcinoma cell line (Moscow et al, 1988).
  • Human melanoma * tissue excised from a patient and frozen in liquid nitrogen before assay of enzyme activity.
  • phosphate buffered saline PBS
  • EDTA EDTA
  • Cells were collected by centrifugation (3 minutes at 2000 rpm), resuspended in 5 volumes of the appropriate extraction buffer and
  • the homogenate was stored on ice for the duration of the experiment.
  • the enzyme was assayed by an adaptation of the method of Stanley et al. (1984). Measurements
  • Flasks were gassed with oxygen for 30 seconds and incubated, stoppered, for 120 minutes before the injection through the seal of 0.2 mis of 25 % perchloric acid and cooling on ice.
  • the medium was neutralised to pH 7 with 40 % potassium hydroxide before being assayed for metabolites.
  • Glucose concentration was estimated by the method of Bergmeyer et al. (1974).
  • Cells were cultured as normal in Minimal Essential Medium with foetal calf serum, glutamine and antibiotics and an appropriate concentration of mannoheptulose, sedoheptulose or galactose. Each flask was inocculated with an equal volume of cell- suspension. Cells were extracted in phosphate buffered saline at 24 hour intervals and total cell numbers determined per flask by visual inspection of an aliquot of cell-suspension in a Neubauer Improved cell-counting chamber. Nutrients in the medium were not exhausted and the cell-population did not reach confluence over the 5 day period of the growth experiment. Incorporation of 3 H-Thymidine
  • ICRF ICRF
  • the animals developed visible tumours within 3 - 5 days which increased in size over the subsequent 15 - 20 days.
  • the final tumour burden never exceeded 5 % of the animal's body weight.
  • the animals ate and drank normally during the tumour-bearing period.
  • Rates of consumption of glucose in the presence and absence of mannoheptulose are presented in Table 4.
  • the presence of the inhibitor effects a severe reduction in the rate of glucose consumption for the tumorigenic cell-lines.
  • Percentage inhibition is 25 and 47 % for HEp 2 and ESH TR1-2 cell-lines, respectively, at 30 mM mannoheptulose.
  • Rates of growth of cells cultured in minimal essential medium in the presence of mannoheptulose are shown in figures 1 to 4. Concentrations of inhibitor used were 0, 20 and 100 mM. A severe inhibition of the rate of growth is achieved. Percentage inhibition ranges from 75 to 91 % at 100 mM mannoheptulose and 35 to 65 % at 20 mM, as the curve presented in figure 5 shows.
  • Table 8 shows that glucokinase activity is present in samples of malignant melanoma tumour, surgicallly removed from patients in a British
  • the range of activities (1.67 to 9.07 nmol/minute/mg protein) is smaller than for the cultured cell-lines which suggests that the magnitude of the activity may be a characteristic of a given tumour-type (in this case melanoma), regardless of source.
  • Glucokinase activities from all melanoma samples are inhibited by 10mM mannoheptulose (a very low dose) and this suggests that this dose would inhibit rates of growth.
  • Table 10 shows the concentrations of various of the compounds from Table 7 required to bring about a 50% reduction in growth rate of a range of cultured human cell-lines. All compounds so far tested which inhibit glucokinase activity also inhibit growth rates of tumour cells. The compounds listed on Table 10 have all been screened for inhibition of growth of the normal, non-tumorigenic cell-line, MRC5 (a diploid fibroblast from a human embryonic lung). None of the compounds affected growth of this cell-line at
  • glucokinase inhibitor mannoheptulose
  • Suppressed cells in this context, may represent a pre-malignant state. These cells have acquired immortality in culture, but fail to show the uncontrolled proliferation necessary for tumour production. Growth rates of normal, non-tumorigenic cell-lines are unaffected by this compound. In the case of the non-tumorigenic cell-line used during the present work, a human diploid fibroblast, this is almost certainly due to the absence of
  • tumour growth inhibitor such as
  • mannoheptulose could reinforce the more conventional treatments.
  • extrahepatic cancers the majority of human cancers are epithelial carcinomas.
  • the assay of this activity is sensitive and can be performed quickly with
  • Mannoheptulose inhibits growth of human tumour cell-lines both in culture and of the two bladder cancer cell-lines studied in the nude mouse. The specificity of this effect in vivo is indicated by the much weaker inhibition of growth of the rat carcinoma which is predicted by the lower level of glucokinase activity evinced by these cells.
  • mannoheptulose required for inhibition of growth rate in the cells of the present study are relatively high. Inhibition ceases to be consistently significant below a concentration of about 5 mM (equivalent to approximately 1 g per kg body weight). This is probably owing to the relatively low affinity of glucokinase for this inhibitor. Rat liver glucokinase has a K i for mannoheptulose of 12.5 mM. However, it is possible that modification of the chemical structure of mannoheptulose may result in more efficient inhibition. This would result in lower doses being required for inhibition of tumour growth rate while retaining the non-toxicity of the parent
  • Methods of Assessing Inhibition of Glucokinase Activity Requirements include a sample of tissue known to have glucokinase activity, such as rat liver or one of the cell-lines mentioned above. The sample is homogenised and glucokinase activity is assayed by the method described above in the section headed "Assay of Glucokinase Activity". Inclusion of an appropriate concentration of a putative inhibitor and comparison with the activity measured in its absence will give an indication of its inhibitory properties.
  • nd denotes glucokinase activity non-detectable.
  • I 50 represents the concentration required to elicit 50 % inhibition of growth rate in culture. All compounds inhibit glucokinase activity in the same cell-lines.
  • Transporter mRNA are Induced by ras or src oncogenes" Science 235 pp1492 - 1495 (1987).
  • Bramwell, M.E. and Harris, H. "An abnormal membrane glycoprotein associated with malignancy in a wide range of different tumours” Proc. Royal Soc. B201 pp87 - 106 (1978).
  • Neoplastic Cells D.Phil Thesis, University of Oxford (1990) (b).

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
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  • Animal Behavior & Ethology (AREA)
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  • Steroid Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne un procédé d'inhibition de la croissance de cellules tumorales qui consiste à mettre ces dernières en contact avec un inhibiteur de la glucokinase. L'enzyme glucokinase que l'on ne trouve que dans les cellules-β du foie et du pancréas s'avère active dans les cellules tumorales.
PCT/GB1994/001676 1993-07-30 1994-08-01 Inhibiteurs de tumeurs WO1995003809A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU72692/94A AU7269294A (en) 1993-07-30 1994-08-01 Use of glucokinase inhibitors for the manufacture of a medicament for treating tumours

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9315846.7 1993-07-30
GB939315846A GB9315846D0 (en) 1993-07-30 1993-07-30 Tumour inhibitors

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Publication Number Publication Date
WO1995003809A2 true WO1995003809A2 (fr) 1995-02-09
WO1995003809A3 WO1995003809A3 (fr) 1995-03-16

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1666046A1 (fr) * 2003-09-17 2006-06-07 Third Military Medical University Chinese People's Liberation Army P.R. of China Utilisation de la n-acetyl-d-aminoglycosamine pour la preparation de medicaments de traitement du cancer et des metastases
EP1757296A1 (fr) * 2004-05-26 2007-02-28 National University Corporation Kagawa University Procédé de contrôle de la prolifération de cellules endothéliales vasculaires et empêchant la formation lumière
US7666459B2 (en) 2001-09-12 2010-02-23 The Procter & Gamble Company Pet food compositions
EP2159230A1 (fr) 2000-08-07 2010-03-03 Centocor Ortho Biotech Inc. Anticorps anti-TNF, compositions, procédés et utilisations
US7897579B2 (en) 2004-04-30 2011-03-01 Laboratoires Expanscience Use of a compound comprising D-mannoheptulose and/or perseitol for treating and preventing innate immunity modification diseases
WO2011073281A1 (fr) 2009-12-16 2011-06-23 Laboratoires Expanscience Composition comprenant au moins un sucre en c7 pour le traitement de l'alopécie, pour le traitement cosmétique des phanères, et pour le soin des cheveux, cils ou ongles
WO2012012390A1 (fr) 2010-07-19 2012-01-26 Marvphyt Development Llc Composition botanique et procédés de fabrication et utilisation
US8563522B2 (en) 1997-07-08 2013-10-22 The Iams Company Method of maintaining and/or attenuating a decline in quality of life
US8563730B2 (en) 2008-05-16 2013-10-22 Takeda San Diego, Inc. Pyrazole and fused pyrazole glucokinase activators
WO2014122326A1 (fr) 2013-02-11 2014-08-14 Laboratoires Expanscience Utilisation d'une composition comprenant un perséose d'avocat dans la protection des cellules souches épidermiques
US9771199B2 (en) 2008-07-07 2017-09-26 Mars, Incorporated Probiotic supplement, process for making, and packaging
US9821015B2 (en) 2003-12-19 2017-11-21 Mars, Incorporated Methods of use of probiotic bifidobacteria for companion animals
US10104903B2 (en) 2009-07-31 2018-10-23 Mars, Incorporated Animal food and its appearance

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050158294A1 (en) 2003-12-19 2005-07-21 The Procter & Gamble Company Canine probiotic Bifidobacteria pseudolongum
AU2006253006B8 (en) 2005-05-31 2011-09-15 Alimentary Health Ltd Feline probiotic Lactobacilli
BRPI0611492B1 (pt) 2005-05-31 2021-10-13 Mars, Incorporated Bifidobactéria probiótica felina
ES2551719T3 (es) 2007-02-01 2015-11-23 Iams Europe B.V. Procedimiento para disminuir la inflamación y el estrés en un mamífero usando antimetabolitos de glucosa, aguacate o extractos de aguacate

Citations (2)

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EP0249008A2 (fr) * 1986-05-09 1987-12-16 Pulverer, Gerhard, Prof. Dr.Dr.h.c. Utilisation de monosaccharides spécifiques pour la préparation d'un médicament pour la prévention des métastases de tumeurs malignes
EP0372730A2 (fr) * 1988-11-18 1990-06-13 University Of British Columbia N-acétylglucosamine comme agent cytoprotectif

Patent Citations (2)

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EP0249008A2 (fr) * 1986-05-09 1987-12-16 Pulverer, Gerhard, Prof. Dr.Dr.h.c. Utilisation de monosaccharides spécifiques pour la préparation d'un médicament pour la prévention des métastases de tumeurs malignes
EP0372730A2 (fr) * 1988-11-18 1990-06-13 University Of British Columbia N-acétylglucosamine comme agent cytoprotectif

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Title
BIOCHEM. CELL BIOL., vol.67, no.6, 1989 pages 311 - 314 D.HERNANDEZ ET AL. 'Mannose toxicity in Ehrlich ascites tumor cells' *
BIOLOGICAL REVIEWS, vol.50, no.2, 1975 pages 129 - 165 KEDAR N. PRASAD 'Differentiation of neuroblastoma cells in culture' *
ENDOCRINOLOGY, vol.124, no.5, 1989 pages 2350 - 2357 WALTER S. ZAWALICH ET AL. 'Interleukin-1alpha excerts glucose-dependent stimulatory and inhibitory effects on islet cell phosphoinositide hydrolysis and insulin secretion' *
EUR.J.BIOCHEM, vol.145, no.1, 1984 pages 163 - 171 MARIA LUZ CARDENAS ET AL. 'Suppression of kinetic cooperativity of hexokinase D (glucokinase) by competitive inhibitors' *

Cited By (25)

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US8563522B2 (en) 1997-07-08 2013-10-22 The Iams Company Method of maintaining and/or attenuating a decline in quality of life
EP2159230A1 (fr) 2000-08-07 2010-03-03 Centocor Ortho Biotech Inc. Anticorps anti-TNF, compositions, procédés et utilisations
US8728559B2 (en) 2001-09-12 2014-05-20 The Iams Company Pet food compositions
US8663729B2 (en) 2001-09-12 2014-03-04 The Iams Company Pet food compositions
US7666459B2 (en) 2001-09-12 2010-02-23 The Procter & Gamble Company Pet food compositions
JP2007506645A (ja) * 2003-09-17 2007-03-22 中国人民解放▲軍▼第三▲軍▼医大学 抗腫瘍および抗転移のための製剤の製造におけるｎ−アセチル−ｄ−グルコサミンの使用
EP1666046A4 (fr) * 2003-09-17 2007-10-03 Univ Pla 3Rd Military Medical Utilisation de la n-acetyl-d-aminoglycosamine pour la preparation de medicaments de traitement du cancer et des metastases
EP1666046A1 (fr) * 2003-09-17 2006-06-07 Third Military Medical University Chinese People's Liberation Army P.R. of China Utilisation de la n-acetyl-d-aminoglycosamine pour la preparation de medicaments de traitement du cancer et des metastases
US9821015B2 (en) 2003-12-19 2017-11-21 Mars, Incorporated Methods of use of probiotic bifidobacteria for companion animals
US9023810B2 (en) 2004-04-30 2015-05-05 Laboratories Expanscience Use of a compound comprising D-mannoheptulose and/or perseitol for treating and preventing innate immunity modification diseases
US7897579B2 (en) 2004-04-30 2011-03-01 Laboratoires Expanscience Use of a compound comprising D-mannoheptulose and/or perseitol for treating and preventing innate immunity modification diseases
JP4943839B2 (ja) * 2004-05-26 2012-05-30 株式会社希少糖生産技術研究所 血管新生抑制剤
EP1757296A4 (fr) * 2004-05-26 2010-09-01 Rare Sugar Production Technica Procédé de contrôle de la prolifération de cellules endothéliales vasculaires et empêchant la formation lumière
EP1757296A1 (fr) * 2004-05-26 2007-02-28 National University Corporation Kagawa University Procédé de contrôle de la prolifération de cellules endothéliales vasculaires et empêchant la formation lumière
US8563730B2 (en) 2008-05-16 2013-10-22 Takeda San Diego, Inc. Pyrazole and fused pyrazole glucokinase activators
US9139598B2 (en) 2008-05-16 2015-09-22 Takeda California, Inc. Glucokinase activators
US9771199B2 (en) 2008-07-07 2017-09-26 Mars, Incorporated Probiotic supplement, process for making, and packaging
US10709156B2 (en) 2008-07-07 2020-07-14 Mars, Incorporated Pet supplement and methods of making
US10104903B2 (en) 2009-07-31 2018-10-23 Mars, Incorporated Animal food and its appearance
US8894979B2 (en) 2009-12-16 2014-11-25 Laboratoires Expanscience Composition containing at least one C7 sugar for alopecia treatment, cosmetic treatment of hair and nails, and care of hair, eyelashes, or nails
US9616009B2 (en) 2009-12-16 2017-04-11 Laboratoires Expanscience Composition containing at least one C7 sugar for alopecia treatment, cosmetic treatment of hair and nails, and care of hair, eyelashes or nails
WO2011073281A1 (fr) 2009-12-16 2011-06-23 Laboratoires Expanscience Composition comprenant au moins un sucre en c7 pour le traitement de l'alopécie, pour le traitement cosmétique des phanères, et pour le soin des cheveux, cils ou ongles
WO2012012390A1 (fr) 2010-07-19 2012-01-26 Marvphyt Development Llc Composition botanique et procédés de fabrication et utilisation
WO2014122326A1 (fr) 2013-02-11 2014-08-14 Laboratoires Expanscience Utilisation d'une composition comprenant un perséose d'avocat dans la protection des cellules souches épidermiques
US10092495B2 (en) * 2013-02-11 2018-10-09 Laboratoire Expanscience Use of a composition comprising avocado perseose in the protection of epidermal stem cells

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AU7269294A (en) 1995-02-28
GB9315846D0 (en) 1993-09-15
WO1995003809A3 (fr) 1995-03-16

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