WO2002072086A2 - Use of epigallocatechin-3-gallate or its derivatives in the prevention and treatment of neurodegenerative diseases - Google Patents
Use of epigallocatechin-3-gallate or its derivatives in the prevention and treatment of neurodegenerative diseases Download PDFInfo
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- WO2002072086A2 WO2002072086A2 PCT/IT2002/000149 IT0200149W WO02072086A2 WO 2002072086 A2 WO2002072086 A2 WO 2002072086A2 IT 0200149 W IT0200149 W IT 0200149W WO 02072086 A2 WO02072086 A2 WO 02072086A2
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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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the present invention relates to the use of a compound or its derivatives in the prevention and treatment of neurodegenerative diseases.
- Neurodegenerative diseases are a significant problem at a socio-economic and health level. Reference may be made to Parkinson's disease and Alzheimer's disease, which are the main causes of dementia in the population of America and Europe, Creutzfeldt-Jacob syndrome caused by prion, and sleeping sickness caused by protozoa, including Trypanosoma brucei rhodensiense and Trypanosoma brucei gambiense. Sleeping sickness is one of the main causes of death in the African population.
- Neurodegenerative disease are caused by the death of nerve cells, for example astrocytes, astroglia and neurons. These nerve cell degenerative processes are linked to the action of interferon- ⁇ (IFN- ⁇ ) (Galimberti D. et al. (1999) Biochem. Biophys . Res. Comm. 263, 251-256; Hunot S. et al. (1999) J. Neurosci. 19 3440-3447; Blasko I. et al. (1999) FAsEB J. 13 63-68; Suo Z. et al . (1998) Brain Res. 807 110-117; Delgado et al.(1998) J. Leukoc . Biol.
- IFN- ⁇ interferon- ⁇
- interferon- ⁇ is a cause of the onset of neurodegenerative diseases.
- the present invention also relates to the use of compounds with the following formula (I), or its derivatives in the prevention and treatment of neurodegenerative diseases: (I)
- the compounds according to the present invention are normally used in the in vitro experiments (see the examples) in doses of between 1 and 50 ⁇ M, preferably from 5 to 20 ⁇ M, in a DME culture, complete with 10% v/v of fetal bovine serum.
- the inhibitory action of the compounds according to the present invention in the neurodegenerative processes described above is not attributable to the anti-oxidant , anti-inflammatory or anti-tumor activity of the compounds with formula (I).
- Vitamin C was used as the anti-oxidant. This compound was not active even at a dose of 100 ⁇ M.
- the anti-inflammatory compound used was hydrocortisone , a steroidal anti- inflammatory drug. This compound was also inactive, even at a dose of 100 ⁇ M.
- the non-steroidal anti-inflammatory drug Ibuprofen was used, and was not active at a dose of 400 ⁇ M.
- the anti-tumor compound used was cisplatin, which was not active at a dose of 17 ⁇ M.
- the Applicant demonstrated that in order to inhibit STATl activity, the structure of the compounds with formula (I) is specific: neither gallic acid nor epigallo- catechin, which are the two polyphenolic components of EGCG, have a STATl inhibitory action.
- Epigallocatechin-3-gallate is available on the market. It is the main ingredient of green tea extract. The methods for its isolation are indicated in Merck Index Edition 12 in the above-mentioned literature.
- compositions containing the compounds according to the present invention contain the usual vehicles and excipients. They may be in the form of tablets, capsules or in formulations suitable for parenteral administration.
- Effective doses of the compounds according to the present invention are those typically used in clinical medicine for epigallocatechin-3-gallate, or lower.
- compositions containing the compounds according to the present invention can be prepared using techniques well known to experts in the field. See, for example, “Remington's Pharmaceutical Sciences 15 " ⁇ Ed.”
- Activation of the STATl system also plays an important part in other diseases, such as asthma (Guo F.H. et al. J. Immunol. 2000, 164(11) 6970-80; Sampath e al . , J. Clin. Invest. 1999, 103(9) 1353-61), diabetes (Hill N.J. et al., Diabetes 2000 49(10) 1744-7; Sekine N. et al . J. Cell Physiol. 2000 184(1) 46-57), cardiovascular diseases (J. Biol. Chem. 2000 275 10002-8), obesity (Scarpace P.J et al., Neuropharmacology 2000, 39(10) 1872-9; Velloso L.A. et al. Cardiovasc. Res. 1998 272(26) 16216-23).
- the products according to the present invention can also be used to treat these diseases.
- STATl activation was measured by means of EMSA (elec- trophoretic mobility shift assay).
- 10 tg of nuclear extract (Osborn, L., unkel, S., and Nabel, G.J. (1989) Proc . Natl . Acad. Sci . USA 86, 2336-2340) were incubated at room temperature for 20 minutes with [ 32 P]- double- stranded oligonucleotide ( 5 ' -gtegaCATTTCCCCGTAAATCg-3 ' ) (Wagner, B.J., Hayes, T.E.f Hoban, C.J., and Cochran, B.H. (1990) EMBO J. 9, 4477-4484).
- the products were fraction- ated by means of electrophoresis on non-denaturing poly- acrylamide gel.
- the intensity of the delayed bands was measured using the Phosphorimager system (Molecular Dynamics, Sunnyvale, CA, USA).
- Example 1 was repeated, but with a concentration of 2 ⁇ M in the DMEM culture.
- Example 1 was repeated, but with a concentration of 5 ⁇ M in the DMEM culture .
- Example 1 was repeated, but with a concentration of 10 ⁇ M in the DMEM culture. The results are indicated in example 27.
- Example 1 was repeated, but with a concentration of 20 ⁇ M in the DMEM culture.
- Example 1 was repeated, but with a concentration of 50 ⁇ M in the DMEM culture.
- hydrocortisone was used as a steroidal anti-inflammatory compound for comparison, in concentrations of 10 ⁇ M, 20 ⁇ M, 50 ⁇ M and 100 ⁇ M in the DMEM culture. The results are indicated in example 27.
- ibuprofen was used as a non- steroidal anti-inflammatory compound for comparison, in concentrations of 10 ⁇ M, 50 ⁇ M, 100 ⁇ M, 200 ⁇ M and 400 ⁇ M in the DMEM culture .
- cisplatin was used as an anti-tumor compound for comparison, in ⁇ M concentrations in the DMEM culture .
- Examples 1 to 6 were repeated, but using epigallo- catechin as the active compound in place of EGCG.
- Epigal- locatechin is one of the two polyphenolic components of EGCG. The results are indicated in example 27.
- EXAMPLE 25 Comparison
- Example 1 was repeated, but using Interleukin 6 (IL-1)
- Interleukin 6 is a known STAT3 activator.
- HeLa human cell lines human cervical tumor cells were also used; or HepG2 human liver tumor cell lines; or MCF7 human breast tumor cell lines.
- the compound to be tested was EGCG (50 ⁇ M) , the com- pound with formula (I) according to the present invention.
- IFN- ⁇ rapidly induces strong STATl activation in the U251 human glioblastoma cell line.
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Abstract
An epigallocatechni-3-gallate compound with the following formula (I), or its derivatives, is used for the prevention and treatment of neurodegenerative diseases, like for example of Parkinson's disease, Alzheimer's disease, Creutzfeld-Jacob syndrome, sleeping sickness caused by protozoa, including Trypanosoma brucei rhodensiense and Trypanosoma brucei gambiense, as well as for the treatment of asthma, diabetes, cardiovascular diseases, obesity.
Description
USE OF EPOG ALLOC ATECHIN-3 -GALL ATE OR DERIVATIVES THEREOF IN THE PROPHYLAXIS AND TREATMENT OF NEURODEGENERATIVE DISEASES
TECHNICAL FIELD
The present invention relates to the use of a compound or its derivatives in the prevention and treatment of neurodegenerative diseases.
Neurodegenerative diseases are a significant problem at a socio-economic and health level. Reference may be made to Parkinson's disease and Alzheimer's disease, which are the main causes of dementia in the population of America and Europe, Creutzfeldt-Jacob syndrome caused by prion, and sleeping sickness caused by protozoa, including Trypanosoma brucei rhodensiense and Trypanosoma brucei gambiense. Sleeping sickness is one of the main causes of death in the African population.
The drugs currently available for the treatment of neurodegenerative diseases do not allow effective thera- pies and, therefore, the pharmacological treatment of these diseases is unsatisfactory.
Neurodegenerative disease are caused by the death of nerve cells, for example astrocytes, astroglia and neurons. These nerve cell degenerative processes are linked to the action of interferon-γ (IFN-γ) (Galimberti D. et al. (1999) Biochem. Biophys . Res. Comm. 263, 251-256; Hunot S. et al. (1999) J. Neurosci. 19 3440-3447; Blasko I. et al. (1999) FAsEB J. 13 63-68; Suo Z. et al . (1998) Brain Res. 807 110-117; Delgado et al.(1998) J. Leukoc . Biol. 63 740- 745; Rossi F, Bianchini E. (1996) Biochem. Biophys. Res. Co~un. 225 474-478; MedaL. et al (1995) Nature 374, 647-
650) which, by activating a nuclear factor STAT1 (Signal transducers and activators of transcription 1), carries out the various pleiotropic actions (Boehm, U. et al.(1997) Annu. Rev. Immunol. 15, 749-795; ordula T. et al. (1998) J. Biol. Chem. 273 4112-4118; Kitamura Y. et al Neurosci. Lett. 237 17-20). Amongst the various actions of interferon-γ in the cell, of particular importance is its ability to modulate the expression of an enzyme, inducible nitric oxide synthase ( iNOS ) , which by producing large quantities of NO can kill off nerve cells. This explains why interferon-γ is a cause of the onset of neurodegenerative diseases.
The need was felt for the availability of drugs for the prevention and treatment of neurodegenerative diseases, which would be particularly effective in inhibiting the activation of STATl.
This technical problem was solved by using the compound epigallocatechin-3-gallate, or its derivatives.
As a result, the present invention also relates to the use of compounds with the following formula (I), or its derivatives in the prevention and treatment of neurodegenerative diseases:
(I)
The activity of compounds with the formula (I) in neurodegenerative diseases was demonstrated in the present invention by means of an experimental in vitro model, us- ing U251 human glioblastoma cells. In this experiment it was demonstrated that, for example using epigallocatechin- 3-gallate (EGCG) as the invention compound, in a concentration of 5 μM, the invention compounds are effective in the treatment of neurodegenerative diseases, inhibiting 50% of the maximal activation of STATl induced by interferon-γ.
The compounds according to the present invention are normally used in the in vitro experiments (see the examples) in doses of between 1 and 50 μM, preferably from 5 to 20 μM, in a DME culture, complete with 10% v/v of fetal bovine serum.
The Applicant found that STATl inhibition normally occurs in a dose-dependent manner.
The inhibitory action of the compounds according to the present invention in the neurodegenerative processes described above is not attributable to the anti-oxidant , anti-inflammatory or anti-tumor activity of the compounds with formula (I). Effectively, using U251 human glioblastoma cells it was demonstrated that anti-oxidant, anti- inflammatory or anti-tumor drugs cannot inhibit activation of STATl induced by interferon-γ (see the examples). Vitamin C was used as the anti-oxidant. This compound was not active even at a dose of 100 μM. The anti-inflammatory compound used was hydrocortisone , a steroidal anti- inflammatory drug. This compound was also inactive, even
at a dose of 100 μM. The non-steroidal anti-inflammatory drug Ibuprofen was used, and was not active at a dose of 400 μM. The anti-tumor compound used was cisplatin, which was not active at a dose of 17 μM. The Applicant demonstrated that in order to inhibit STATl activity, the structure of the compounds with formula (I) is specific: neither gallic acid nor epigallo- catechin, which are the two polyphenolic components of EGCG, have a STATl inhibitory action. Epigallocatechin-3-gallate is available on the market. It is the main ingredient of green tea extract. The methods for its isolation are indicated in Merck Index Edition 12 in the above-mentioned literature.
Pharmaceutical formulations containing the compounds according to the present invention contain the usual vehicles and excipients. They may be in the form of tablets, capsules or in formulations suitable for parenteral administration.
Effective doses of the compounds according to the present invention are those typically used in clinical medicine for epigallocatechin-3-gallate, or lower.
Pharmaceutical formulations containing the compounds according to the present invention can be prepared using techniques well known to experts in the field. See, for example, "Remington's Pharmaceutical Sciences 15"^ Ed."
Activation of the STATl system also plays an important part in other diseases, such as asthma (Guo F.H. et al. J. Immunol. 2000, 164(11) 6970-80; Sampath e al . , J. Clin. Invest. 1999, 103(9) 1353-61), diabetes (Hill N.J. et al., Diabetes 2000 49(10) 1744-7; Sekine N. et al . J.
Cell Physiol. 2000 184(1) 46-57), cardiovascular diseases (J. Biol. Chem. 2000 275 10002-8), obesity (Scarpace P.J et al., Neuropharmacology 2000, 39(10) 1872-9; Velloso L.A. et al. Cardiovasc. Res. 1998 272(26) 16216-23). The products according to the present invention can also be used to treat these diseases.
The following examples illustrate the present invention without limiting the scope of application.
EXAMPLE 1 The cell line of U251 human glioblastoma was cultivated, at 37°C, in a DMEM 12-614 (Dulbecco's modified eagle medium Bio hittaker Co.) culture complete with 10% of fetal bovine serum. The serum was eliminated 4 hours before treatment with interferon-γ (250 U/ml). The epigallocate- chin gallate concentration (R = H, indicated as EGCG) used was 1 μM in the DMEM culture.
STATl activation was measured by means of EMSA (elec- trophoretic mobility shift assay). 10 tg of nuclear extract (Osborn, L., unkel, S., and Nabel, G.J. (1989) Proc . Natl . Acad. Sci . USA 86, 2336-2340) were incubated at room temperature for 20 minutes with [32P]- double- stranded oligonucleotide ( 5 ' -gtegaCATTTCCCCGTAAATCg-3 ' ) (Wagner, B.J., Hayes, T.E.f Hoban, C.J., and Cochran, B.H. (1990) EMBO J. 9, 4477-4484). The products were fraction- ated by means of electrophoresis on non-denaturing poly- acrylamide gel. The intensity of the delayed bands was measured using the Phosphorimager system (Molecular Dynamics, Sunnyvale, CA, USA).
The results are indicated in example 27. EXAMPLE 2
Example 1 was repeated, but with a concentration of
2 μM in the DMEM culture.
The results are indicated in example 27.
EXAMPLE 3 Example 1 was repeated, but with a concentration of 5 μM in the DMEM culture .
The results are indicated in example 27.
EXAMPLE 4 Example 1 was repeated, but with a concentration of 10 μM in the DMEM culture. The results are indicated in example 27.
EXAMPLE 5 Example 1 was repeated, but with a concentration of 20 μM in the DMEM culture.
The results are indicated in example 27. EXAMPLE 6
Example 1 was repeated, but with a concentration of 50 μM in the DMEM culture.
The results are indicated in example 27. EXAMPLES 7-10 comparison with an anti-oxidant compound In these examples vitamin C was used as an anti- oxidant compound for comparison, in concentrations of 10 μM, 20 μM, 50 μM and 100 μM in the DME culture. The results are indicated in example 27.
EXAMPLES 11-14 Comparison with a steroidal anti-inflammatory compound
In these examples hydrocortisone was used as a steroidal anti-inflammatory compound for comparison, in concentrations of 10 μM, 20 μM, 50 μM and 100 μM in the DMEM culture.
The results are indicated in example 27.
EXAMPLES 15-19 Comparison with a non-steroidal anti-inflammatory compound
In these examples ibuprofen was used as a non- steroidal anti-inflammatory compound for comparison, in concentrations of 10 μM, 50 μM, 100 μM, 200 μM and 400 μM in the DMEM culture .
The results are indicated in example 27. EXAMPLES 20-23 Comparison with an anti-tumor compound
In these examples cisplatin was used as an anti-tumor compound for comparison, in μM concentrations in the DMEM culture .
The results are indicated in example 27. EXAMPLE 24 Comparison
Examples 1 to 6 were repeated, but using epigallo- catechin as the active compound in place of EGCG. Epigal- locatechin is one of the two polyphenolic components of EGCG. The results are indicated in example 27. EXAMPLE 25 Comparison
Examples 1 to 6 were repeated, but using gallic acid as the active compound in place of EGCG. Gallic acid is the second polyphenolic compound of EGCG. The results are indicated in example 27. EXAMPLE 26 Comparison
Example 1 was repeated, but using Interleukin 6 (IL-
6) instead of IFN-1 as the STATl activator. Interleukin 6 is a known STAT3 activator. HeLa human cell lines (human cervical tumor cells) were also used; or HepG2 human liver tumor cell lines; or MCF7 human breast tumor cell lines.
The compound to be tested was EGCG (50 μM) , the com-
pound with formula (I) according to the present invention.
EXAMPLE 27 Results
IFN-γ rapidly induces strong STATl activation in the U251 human glioblastoma cell line.
All of the compounds according to the present invention and those used for comparisons are added to the U251 cell culture half an hour before treatment with IFN-γ.
Claims
A use, for the prevention and treatment of neurodegenerative diseases, of an epigallocatechin-3-gallate compound with the following formula (I), or its derivatives :
(I) A use according to claim 1, in the prevention and specific treatment of Parkinson's disease, Alz- heimer's disease, Creutzfeldt-Jacob syndrome, sleeping sickness caused by protozoa, including Trypanosoma brucei rhodensiense and Trypanosoma brucei gam- biense. , A use according to claim 1, in the prevention and specific treatment of asthma, diabetes, cardiovascular diseases, obesity. A use according to any of the foregoing claims, for the inhibition of STATl (Signal transducers and activators of transcription 1) maximal activation induced by interferon-γ. A use according to any of the foregoing claims, in which the compound is produced in the form of tablets, capsules or in formulations suitable for par- enteral administration.
A use according to any of the foregoing claims, in which the effective doses of the above-mentioned compound are those typically used in clinical medicine for epigallocatechin-3-gallate, or lower.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2002247973A AU2002247973A1 (en) | 2001-03-12 | 2002-03-11 | Use of epigallocatechin-3-gallate or its derivatives in the prevention and treatment of neurodegenerative diseases |
| EP02717053A EP1411920A2 (en) | 2001-03-12 | 2002-03-11 | Use of epigallocatechin-3-gallate or derivatives thereof in the prophylaxis and treatment of neurodegenerative diseases |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT2001VR000031A ITVR20010031A1 (en) | 2001-03-12 | 2001-03-12 | USE OF EPIGALLOCATECHIN-3-GALLATO OR ITS DERIVATIVES IN THE PROPHYLAXIS AND TREATMENT OF NEURODEGENERATIVE DISEASES. |
| ITVR2001A000031 | 2001-03-12 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| WO2002072086A2 true WO2002072086A2 (en) | 2002-09-19 |
| WO2002072086A8 WO2002072086A8 (en) | 2002-10-10 |
| WO2002072086A3 WO2002072086A3 (en) | 2004-02-19 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IT2002/000149 WO2002072086A2 (en) | 2001-03-12 | 2002-03-11 | Use of epigallocatechin-3-gallate or its derivatives in the prevention and treatment of neurodegenerative diseases |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP1411920A2 (en) |
| AU (1) | AU2002247973A1 (en) |
| IT (1) | ITVR20010031A1 (en) |
| WO (1) | WO2002072086A2 (en) |
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004041257A2 (en) * | 2002-11-07 | 2004-05-21 | Dsm Ip Assets B.V. | Novel nutraceutical compositions comprising epigallocatechin gallate |
| WO2004047926A1 (en) * | 2002-11-28 | 2004-06-10 | Dsm Ip Assets B.V. | Nutraceutical compositions comprising epigallocatechin gallate and raspberry ketone |
| WO2005027661A1 (en) * | 2003-09-23 | 2005-03-31 | Dsm Ip Assets B.V. | Compositions for the treatment and prevention of diabetes mellitus |
| WO2005027901A1 (en) * | 2003-09-25 | 2005-03-31 | Tel Aviv University Future Technology Development L.P. | Compositions and methods using same for treating amyloid-associated diseases |
| EP1877422A1 (en) * | 2005-04-26 | 2008-01-16 | University Of South Florida | Green tea polyphenol alpha secretase enhancers and methods of use |
| US7491699B2 (en) | 2002-12-09 | 2009-02-17 | Ramot At Tel Aviv University Ltd. | Peptide nanostructures and methods of generating and using the same |
| US7504383B2 (en) | 2003-01-07 | 2009-03-17 | Ramot At Tel Aviv University Ltd. | Peptide nanostructures encapsulating a foreign material and method of manufacturing same |
| US7732479B2 (en) | 2004-08-19 | 2010-06-08 | Tel Aviv University Future Technology Development L.P. | Compositions for treating amyloid associated diseases |
| US20120035254A1 (en) * | 2009-04-10 | 2012-02-09 | Kao Corporation | Inhibitor for elevation of gip level |
| US9309247B2 (en) | 2013-03-20 | 2016-04-12 | Lorus Therapeutics Inc. | 2-substituted imidazo[4,5-D]phenanthroline derivatives and their use in the treatment of cancer |
| US10004828B2 (en) | 2005-10-11 | 2018-06-26 | Romat at Tel-Aviv University Ltd. | Self-assembled Fmoc-ff hydrogels |
| WO2019236521A1 (en) * | 2018-06-07 | 2019-12-12 | Avanti Biosciences, Inc. | Methods and formulations for intranasal administration |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8568637B2 (en) | 2004-08-02 | 2013-10-29 | Ramot At Tel-Aviv University Ltd. | Method of forming a fiber made of peptide nanostructures |
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Cited By (18)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2004041257A3 (en) * | 2002-11-07 | 2004-08-05 | Dsm Ip Assets Bv | Novel nutraceutical compositions comprising epigallocatechin gallate |
| WO2004041257A2 (en) * | 2002-11-07 | 2004-05-21 | Dsm Ip Assets B.V. | Novel nutraceutical compositions comprising epigallocatechin gallate |
| WO2004047926A1 (en) * | 2002-11-28 | 2004-06-10 | Dsm Ip Assets B.V. | Nutraceutical compositions comprising epigallocatechin gallate and raspberry ketone |
| JP2006511505A (en) * | 2002-11-28 | 2006-04-06 | ディーエスエム アイピー アセッツ ビー．ブイ． | A novel nutraceutical composition containing epigallocatechin gallate and raspberry ketone |
| US7491699B2 (en) | 2002-12-09 | 2009-02-17 | Ramot At Tel Aviv University Ltd. | Peptide nanostructures and methods of generating and using the same |
| US7504383B2 (en) | 2003-01-07 | 2009-03-17 | Ramot At Tel Aviv University Ltd. | Peptide nanostructures encapsulating a foreign material and method of manufacturing same |
| WO2005027661A1 (en) * | 2003-09-23 | 2005-03-31 | Dsm Ip Assets B.V. | Compositions for the treatment and prevention of diabetes mellitus |
| US7691420B2 (en) | 2003-09-23 | 2010-04-06 | Dsm Ip Assets B.V. | Compositions for the treatment and prevention of diabetes mellitus |
| WO2005027901A1 (en) * | 2003-09-25 | 2005-03-31 | Tel Aviv University Future Technology Development L.P. | Compositions and methods using same for treating amyloid-associated diseases |
| JP2007506732A (en) * | 2003-09-25 | 2007-03-22 | テル アヴィヴ ユニヴァーシティ フューチャー テクノロジー ディヴェロップメント エル．ピー． | Compositions for treating amyloid-related diseases and methods of use thereof |
| US7732479B2 (en) | 2004-08-19 | 2010-06-08 | Tel Aviv University Future Technology Development L.P. | Compositions for treating amyloid associated diseases |
| EP1877422A1 (en) * | 2005-04-26 | 2008-01-16 | University Of South Florida | Green tea polyphenol alpha secretase enhancers and methods of use |
| EP1877422A4 (en) * | 2005-04-26 | 2011-08-10 | Univ South Florida | Green tea polyphenol alpha secretase enhancers and methods of use |
| US20130261045A1 (en) * | 2005-04-26 | 2013-10-03 | University Of South Florida | Green tea polyphenol alpha secretase enhancers and methods of use |
| US10004828B2 (en) | 2005-10-11 | 2018-06-26 | Romat at Tel-Aviv University Ltd. | Self-assembled Fmoc-ff hydrogels |
| US20120035254A1 (en) * | 2009-04-10 | 2012-02-09 | Kao Corporation | Inhibitor for elevation of gip level |
| US9309247B2 (en) | 2013-03-20 | 2016-04-12 | Lorus Therapeutics Inc. | 2-substituted imidazo[4,5-D]phenanthroline derivatives and their use in the treatment of cancer |
| WO2019236521A1 (en) * | 2018-06-07 | 2019-12-12 | Avanti Biosciences, Inc. | Methods and formulations for intranasal administration |
Also Published As
| Publication number | Publication date |
|---|---|
| ITVR20010031A0 (en) | 2001-03-12 |
| AU2002247973A1 (en) | 2002-09-24 |
| WO2002072086A3 (en) | 2004-02-19 |
| EP1411920A2 (en) | 2004-04-28 |
| ITVR20010031A1 (en) | 2002-09-12 |
| WO2002072086A8 (en) | 2002-10-10 |
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