AU2002226652A1 - An anti-atherosclerosis composition containing carotenoids and method for inhibiting LDL oxidation - Google Patents
An anti-atherosclerosis composition containing carotenoids and method for inhibiting LDL oxidationInfo
- Publication number
- AU2002226652A1 AU2002226652A1 AU2002226652A AU2002226652A AU2002226652A1 AU 2002226652 A1 AU2002226652 A1 AU 2002226652A1 AU 2002226652 A AU2002226652 A AU 2002226652A AU 2002226652 A AU2002226652 A AU 2002226652A AU 2002226652 A1 AU2002226652 A1 AU 2002226652A1
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- Prior art keywords
- phytoene
- phytofluene
- ldl
- oxidation
- mixtures
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Description
An Anti-Atherosclerosis Composition Containing Carotenoids and Method for
Inhibiting LDL Oxidation
Field of the Invention
The present invention relates to the field of natural products and uses thereof for inhibiting the progression of atherosclerosis. More particularly, the present invention
relates to compositions comprising phytoene, phytofluene or mixtures thereof and their
use for inhibiting the progression of atherosclerosis.
Background of the Invention
The prevention of LDL oxidation has been acknowledged as an important factor in the
inhibition of the progression of atherosclerosis. There is a variety of anti-atheosclerosis drugs such as the drugs of the vastatin group, hereinafter conventional anti-atherosclerosis
agents. Furthermore, certain carotenoids which are known to be anti-oxidants have been
reported to inhibit LDL oxidation and thus arrest the progression of atherosclerosis (see,
e.g. Krinsky, N., Eree Radical Biology & Medicine, (1989) vol. 7, pp. 617-635 ).
PCT/IL98/00286 discloses the effectiveness of a synergistic mixture of lycopene and
vitamin E in inhibiting LDL-oxidatisn, and hence arresting the progression of
atherosclerosis. The effectiveness of the carotenoids phytoene and phytofluene in inhibiting LDL-oxidation has not been evaluated.
The contribution of atherosclerosis to heart disease is well known. Therefore there is a constant need for novel compositions which effectively inhibit the progression of
•atherosclerosis.
Accordingly, it is an objective of the present invention to provide a novel composition
which demonstrates high effectiveness in inhibiting LDL oxidation, thus effectively arresting the progression of atherosclerosis.
A further objective of the present invention is to provide a method for inhibiting LDL
oxidation and hence inhibit the progression of atherosclerosis.
Other objects of the invention will become apparent as the description proceeds.
Summary of the Invention
The present invention provides a method for inhibiting the progression of atherosclerosis,
comprising the administration of an effective anti-LDL-oxidation amount of phytoene, phytofluene or mixtures thereof, to a subject in need thereof.
Further provided by the present invention is the use of a composition comprising
phytoene, phytofluene or mixtures thereof, for inhibiting the oxidation of LDL.
A further aspect of the present invention is the use of phytoene, phytofluene or mixtures
thereof, in the preparation of a medicament for inhibiting the oxidation of LDL and the
progression of atherosclerosis.
The present invention further provides an anti-atherosclerosis composition comprising a
•LDL-oxidation inhibiting effective amount of phytoene, phytofluene or mixtures thereof.
Further provided by the present invention is the use of a LDL-oxidation inhibiting
effective amount of phytoene, phytofluene or mixtures thereof, in functional foods,
dietary supplements, food stuff and drinks.
Description of the Drawings
Fig. 1(A),(B) - Effect of crystalline natural lycopene and of tomato oleoresin on copper
ion-induced LDL oxidation.
Fig. 2 (A),(B)- Effect of phytofluene/phytoene on copper ion-induced LDL oxidation.
Fig. 3 - Effect of lycopene, vitamin E, β-carotene, and phytofluene/phytoene on LDL
oxidation.
Fig. 4 - Effect of lycoepene in combination with antioxidants on LDL oxidation.
Fig. 5 - Effect of β-Carotene in combination with antioxidants on LDL oxidation.
Fig. 6 - Effect of vitamin E in combination with antioxidants on LDL oxidation.
Fig. 7 - Effect of phytofluene/phytoene in combination with antioxidants on LDL oxidation.
Fig. 8 - Effect of combination of antioxidants on LDL oxidation.
Fig. 9 - Effect of carotenoid mixture on LDL oxidation.
Detailed Description of a Preferred Embodiment of the Invention
The following description is illustrative of preferred embodiments of the invention. The
following description is not to be construed as limiting, it being understood that the
skilled person may carry out many obvious variations to the invention.
The description applies to mixtures of phytoene and phytofluene as well as to each one of them separately. Therefore, wherever reference is made to mixtures thereof it is also intended for each of the carotenoids separately as well.
While studying the effect of various carotenoids on LDL oxidation it has been surprisingly found that phytoene, phytofluene or mixtures thereof, are substantially more effective than other carotenoids in inhibiting LDL oxidation.
According to a particular embodiment of the method of the present invention, at least 0.2 mg/day of phytoene, phytofluene or mixtures thereof, are administered to a subject in order to inhibit the oxidation of LDL in the blood and hence arrest the progression of atherosclerosis. Wherein a mixture of said carotenoids is administered, the ratio between phytoene and phytofluene in the mixture is from about 1 :20 to 20:1. Administration may be in daily multiple or single dosages. According to the present method, administration is adopted to achieve an anti-LDL-oxidation effective concentration of phytoene,
phytofluene or mixtures thereof, in the blood, said concentration being at least 0.01 μM.
According to an optional embodiment of the present method, phytoene, phytofluene or mixtures thereof, may be administered in conjunction with conventional anti-atherosclerosis agents.
According to a further aspect of the present invention there is provided a composition comprising an anti-LDL-oxidation effective amount of phytoene, phytofluene or mixtures 'thereof. Said composition comprising at least 0.1 mg of phytoene, phytofluene or
mixtures thereof. The composition may further comprise pharmaceutically acceptable
adjuvant, excipients and additives.
A further embodiment of the present invention relates to a solid dosage form for oral
administration, in the form of a tablet, capsule, hard-shell capsule, soft gel or gelcap,
which contains at least 0.1 mg of phytoene, phytofluene or mixtures thereof.
According to yet a further embodiment of the present invention, the use of phytoene,
phytofluene or mixtures thereof, is provided wherein they are added to functional foods
such as bars, dietary supplements, drinks or other food stuff so that said functional foods,
dietary supplements, food stuff and drink provide an inhibitory effect on LDL-oxidation.
According to the present embodiment the functional food, food stuff, dietary supplement
or drink comprise at least 0.1 mg of of phytoene, phytofluene or mixtures thereof.
The following examples illustrate the substantially improved effectiveness of phytoene
and phytofluene over other carotenoids, in the inhibition of LDL oxidation.
Examples
General Procedures All studied compounds were dissolved in THF to a stock solution of lmg/ml. LDL was
dialyzed for 24 hours against phosphate buffered- saline (PBS) prior to its oxidation to
remove any EDTA that can interfere with the oxidation. LDL (lOOμg protein/ml), was
incubated in the absence (Control) or presence of increasing concentrations of each one of
'the studied compounds, as well as, in various combinations including 2, 3 or the 4
constituents at the desired natural distribution. LDL oxidation was induced by the
addition of 5μM of CuSO , for 2 hours at 37°C. LDL oxidation was terminated by
adding ImM Na2 EDTA and immediate refrigeration at 4°C. The extent of LDL oxidation
was then determined by measuring the amount of thiobarbituric acid reactive substances
(TBARS) and of lipid peroxides (PD) formed. Control LDL was supplemented with only THF.
Example 1; Effect of crystalline natural lycopene and of tomato oleoresin on copper
ion-induced LDL oxidation: Concentration study.
LDL (100 μg of protein/mL) was pre-incubated for 30 minutes at 37°C with increasing
concentrations of crystalline pure lycopene, or with tomato oleoresin (at equivalent
lycopene concentrations), followed by a further incubation for 2 hours at 37°C in the
presence of 5 μmol/L of CuSO4. LDL oxidation was measured by the TBARS (A) or by
the lipid peroxides (B) assays respectively. Results are given as mean ± SD (n=3).
Addition of increasing concentrations of lycopene inhibited copper ion-induced LDL
oxidation moderately, in a dose-dependent manner. A maximal 22% and 27% inhibition
in TBARS (Fig 1 A) and in lipid peroxides (Fig IB) formation, respectively, was obtained
on using 50μmol/L of lycopene. However, addition of tomato oleoresin to the lipoprotein,
inhibited LDL oxidation to a much greater extent (about 90% inhibition), with an IC50
(the concentration needed to inhibit LDL oxidation by 50%) of 8.0 μmol/L and 8.4
μmol L of lycopene equivalents for the inhibition of TBARS (Fig 1A) and of lipid
peroxides. (Fig IB) formation, respectively.
Example 2; Effect of phytofluene/phytoene on copper ion-induced LDL oxidation:
Concentration study.
Phytofluene/phytoene dose-dependently inhibited CuSO -induced LDL oxidation, as
measured by the TBARS 2(A) and by the lipid peroxides assays 2(B), respectively. The
IC50 of Phytofluene/phytoene in the copper ions-induced LDL oxidation is 0.25 μg/ml for
inhibition of TBARS formation and 0.35 μg/ml for inhibition of lipid peroxides
formation, respectively.
Example 3: Effect of lycopene, vitamin E, β-carotene,, and phytofluene/phytoene on
LDL oxidation.
At the low concentration, which mimics the composition of Lyc-O-Mato®, Lycopene
(lOμg/ml), vitamin E (2.5μg/ml) and β-carotene (0.4μg/ml) did not significantly affect
LDL oxidation. In contrast, phytofluene/phytoene (1.2μg/ml) substantially inhibited LDL
oxidation by 85-90% as analyzed by TBARS and lipid peroxides assays.
Example 4: Effect of lycoepene in combination with antioxidants on LDL oxidation.
On using Lycopene (10 μg/ml) in combination with each one of the other antioxidants
separately (2 compound in each study), the addition to lycopene to β-carotene (0.4μg/ml)
or vitamin E (2.5μg/ml) inhibited LDL oxidation (TBARS assay) by 22% and 11%
respectively, in comparison to the effect of lycopene alone, whereas the addition of
phytofluene/phytoene (1.2μg/ml) inhibited LDL oxidation by as much as 95%. These
results, presented in Fig. 4 show that the addition to lycopene of β-carotene or vitamin E
contribute, though minimally, to the inhibition of LDL oxidation, whereas
phytofluen/phytoen posses the highest capacity to act as a most potent inhibitor of LDL
-8-
oxidation (alone, and in combination with lycopene). Similar results were obtained for
LDL oxidation analysis by the lipid peroxides assay.
Example 5: Effect of β-Carotene in combination with antioxidants on LDL
oxidation.
With reference to Fig. 5, on using β-carotene as the major antioxidant alone or in
combination with the other antioxidants, unlike lycopene, it did not affect at all LDL
oxidation alone or in combination with vitamin E. An inhibitory effect (22%) on LDL
oxidation (TBARS) was observed when β-carotene was added in combination with
lycopene and a most potent inhibition of LDL oxidation (98% inhibition, in the TBARS
assay) was obtained on adding β-carotene together with phytofluene/phytoene. Similar
results were obtained for LDL oxidation analyses by the lipid peroxides assay.
Example 6: Effect of vitamin E in combination with antioxidants on LDL oxidation. On using vitamin E as the major antioxidant alone or in combination with the other
antioxidants, the addition of lycopene but not β-carotene, inhibited LDL oxidation by
12% (TBARS assay). The addition of phytofluene/phytoene to vitamin E resulted in a
98% inhibition in LDL oxidation. Similar results were obtained for the lipid peroxides assay as can be seen in Fig. 6.
Example 7: Effect of phytofluene/phytoene in combination with antioxidants on LDL oxidation.
Referring to Fig. 7, phytofluene/phytoene was found to be the most potent antioxidant
among the carotenoids examined, resulting in up to 90% inhibition of LDL oxidation
(TBARS assay). The addition of each of the other antioxidant further reduced LDL
oxidation with the highest contribution observed for lycopene.
Example 8: Effect of combination of antioxidants on LDL oxidation. Analysis of the effect of various combinations of 3 antioxidants together were evaluated.
Only when the phytofluen/phytoene fraction was present, in any of the 3 studied
combinations, a substantial, over 90% inhibition in LDL oxidation was observed. When
lycopene, β-carotene and vitamin E were used in combination, in the absence of
phylofluene/phytoene, only minimal inhibition of LDL oxidation was obtained as shown
for both the TBARS and the lipid peroxide assays in Fig. 8.
Example 9: Effect of a Mixture of Carotenoids on LDL oxidation.
The effect of Lyc-O-M ato was compared to a mixture of carotenoids prepared from the
combination of 5 antioxidant compounds in the following concentrations; lycopene
(lOμg/ml), β-carotene (0.4μg/ml), Vitamin E (2.5μg/ml) and phytoene/phytofluene
(1.2μg/ml). Referring to Fig. 9, Lyc-O-Mato® caused about 70% (TBARS assay)
inhibition in LDL oxidation. The carotenoid mixture inhibitory effect on LDL oxidation
was 96%) (TBARS assay). Similar results were obtained for the lipid peroxides assay.
While embodiments of the invention have been described by way of illustration, it will be
apparent that the invention may be carried out with many modifications, variations and
adaptations, without departing from its spirit or exceeding the scope of the claims.
Claims (28)
1. A method for inhibiting the progression of atherosclerosis, comprising the
administration of an effective anti-LDL-oxidation amount of phytoene, phytofluene or mixtures thereof, to a subject in need thereof.
2. A method according to claim 1 wherein a least 0.2 mg/day are administered to a
subject in need thereof.
3. A method according to claim 1 wherein a mixture of phytoene and phytofluene is
administered.
4. A method according to claim 3 wherein the ratio of phytoene and phytofluene in the
mixture is from about 1:20 to about 20:1.
5. A method according to claim 1 wherein administration is in a daily dose.
6. A method according to claim 1 wherein the phytoene, phytofluene or mixtures thereof, are administered in conjunction with a conventional anti-atherosclerosis
agents.
7. A method according to claim 1 wherein administration is adopted to achieve an anti-LDL-oxidation effective concentration of phytoene, phytofluene or mixtures
thereof, in the blood, said concentration being at least 0.01 μM.
8. An anti-atherosclerosis composition comprising a LDL-oxidation inhibiting effective amount of phytoene, phytofluene or mixtures thereof.
9. A composition according to claim 8 comprising at least 0.1 mg of phytoene.
10. A composition according to claim 8 comprising 0.1 mg of phytofluene.
11. A composition according to claim 8 comprising at least 0.1 mg of a mixture of phytoene and phytofluene.
12. A composition according to claim 11 wherein the ratio of phytoene and phytofluene in the mixture is from about 1 :20 to about 20: 1.
13. A composition according to claim 8 in the form of a solid dosage tablet, capsule, hard-shell capsule, soft gel or gelcap.
14. A composition according to claim 8 comprising a pharmaceutically acceptable adjuvant, excipient or additive.
15. Use of a composition comprising phytoene, phytofluene or mixtures thereof, for inhibiting the oxidation of LDL.
16. Use of a composition according to claim 15 in conjunction with a conventional
anti-atherosclerosis agent.
17. Use of phytoene, phytofluene or mixtures thereof, in the preparation of a medicament for inhibiting the oxidation of LDL and the progression of atherosclerosis.
18. Use according to claim 17 wherein the medicament comprises a LDL-oxidation
inhibiting effective amount of phytoene, phytofluene or mixtures thereof.
19. Use according to claim 18 wherein the medicament comprises at least 0.1 mg of
phytoene.
20. Use according to claim 18 wherein the medicament comprises at least 0.1 mg of
phytofluene.
21. Use according to claim 18 wherein the medicament comprises at least 0.1 mg of a
mixture of phytoene and phytofluene.
22. Use according to claim 21 wherein the ratio of phytoene and phytofluene in the
mixture is from about 1 :20 to about 20: 1.
23. Use of an anti-LDL-oxidation effective amount of phytoene, phytofluene or mixtures
thereof in the preparation of functional foods, dietary supplements, food stuff and
drinks.
24. Use according to claim 23 wherein about 0.1 mg of phytoene, phytofluene or mixtures thereof is added to the functional foods, dietary supplements, food stuff and drinks.
25. A method substantially as described and exemplified.
26. A use substantially as described and exemplified.
27. A composition substantially as described and exemplified.
28. A pharmaceutical composition substantially as described and exemplified.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IL141039A IL141039A (en) | 2001-01-23 | 2001-01-23 | Anti-atherosclerosis composition containing carotenoids and use in the preparation of medicaments for inhibiting ldl oxidation |
| IL141039 | 2001-01-23 | ||
| PCT/IL2002/000053 WO2002058682A2 (en) | 2001-01-23 | 2002-01-21 | An anti-atherosclerosis composition containing carotenoids and method for inhibiting ldl oxidation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU2002226652A1 true AU2002226652A1 (en) | 2003-02-06 |
| AU2002226652B2 AU2002226652B2 (en) | 2006-09-07 |
Family
ID=11075060
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2002226652A Expired AU2002226652B2 (en) | 2001-01-23 | 2002-01-21 | An anti-atherosclerosis composition containing carotenoids and method for inhibiting LDL oxidation |
Country Status (16)
| Country | Link |
|---|---|
| US (2) | US7351746B2 (en) |
| EP (1) | EP1363609B1 (en) |
| JP (2) | JP4405151B2 (en) |
| KR (1) | KR100841238B1 (en) |
| CN (1) | CN1273119C (en) |
| AT (1) | ATE471716T1 (en) |
| AU (1) | AU2002226652B2 (en) |
| BR (1) | BR0206942A (en) |
| CA (1) | CA2435613C (en) |
| DE (1) | DE60236787D1 (en) |
| ES (1) | ES2346047T3 (en) |
| IL (1) | IL141039A (en) |
| NO (1) | NO20033232L (en) |
| PL (1) | PL208263B1 (en) |
| RU (1) | RU2288707C2 (en) |
| WO (1) | WO2002058682A2 (en) |
Families Citing this family (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL141038A (en) * | 2001-01-23 | 2006-10-05 | Lycored Natural Prod Ind Ltd | Use of carotenoids in the preparation of anti-hypertension agents |
| IL141039A (en) * | 2001-01-23 | 2006-10-31 | Lycored Natural Prod Ind Ltd | Anti-atherosclerosis composition containing carotenoids and use in the preparation of medicaments for inhibiting ldl oxidation |
| US20050148517A1 (en) * | 2002-07-29 | 2005-07-07 | Lockwood Samuel F. | Carotenoid ether analogs or derivatives for controlling connexin 43 expression |
| US7375133B2 (en) * | 2002-07-29 | 2008-05-20 | Cardax Pharmaceuticals, Inc. | Pharmaceutical compositions including carotenoid ether analogs or derivatives for the inhibition and amelioration of disease |
| US7763649B2 (en) | 2002-07-29 | 2010-07-27 | Cardax Pharmaceuticals, Inc. | Carotenoid analogs or derivatives for controlling connexin 43 expression |
| US7521584B2 (en) | 2002-07-29 | 2009-04-21 | Cardax Pharmaceuticals, Inc. | Carotenoid analogs or derivatives for the inhibition and amelioration of disease |
| US20050009788A1 (en) * | 2002-07-29 | 2005-01-13 | Lockwood Samuel Fournier | Carotenoid ester analogs or derivatives for controlling connexin 43 expression |
| US7345091B2 (en) | 2002-07-29 | 2008-03-18 | Cardax Pharmaceuticals, Inc. | Carotenoid ether analogs or derivatives for the inhibition and amelioration of disease |
| US7723327B2 (en) | 2002-07-29 | 2010-05-25 | Cardax Pharmaceuticals, Inc. | Carotenoid ester analogs or derivatives for the inhibition and amelioration of liver disease |
| EP1750723A1 (en) * | 2004-04-14 | 2007-02-14 | Hawaii Biotech, Inc. | Carotenoid analogs or derivatives for the inhibition and amelioration of inflammation |
| US20090099061A1 (en) * | 2006-01-27 | 2009-04-16 | Foss Bente J | Synthesis of carotenoid analogs or derivatives with improved antioxidant characteristics |
| IL176668A0 (en) * | 2006-07-02 | 2006-10-31 | Ibr Ltd | Colorless carotenoids for skin whitening |
| US8063101B2 (en) * | 2007-03-23 | 2011-11-22 | Cardax Pharmaceuticals, Inc. | Carotenoid analogs and derivatives for the prevention of platelet aggregation |
| EP2381935B1 (en) * | 2009-01-19 | 2016-06-01 | Lycored Ltd. | Synergistic combinations of carotenoids and polyphenols |
| JP2018528174A (en) * | 2015-08-20 | 2018-09-27 | アイ．ビー．アール．イスラエリ バイオテクノロジー リサーチ リミテッド | Carotenoid composition having antiviral activity and use thereof |
| JP7492222B2 (en) * | 2018-04-18 | 2024-05-29 | 国立大学法人京都大学 | Adiponectin receptor agonist and use thereof, and food composition for activating adiponectin receptor and use thereof |
Family Cites Families (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4046880A (en) | 1976-04-20 | 1977-09-06 | The University Of Virginia | Method of treating hypertension |
| US6132790A (en) * | 1991-09-06 | 2000-10-17 | Betatene Limited | Carotenoid composition |
| RU2095059C1 (en) | 1993-07-27 | 1997-11-10 | Товарищество с ограниченной ответственностью "Инвест" | Method of prophylaxis and treatment of atherosclerosis |
| US5643623A (en) * | 1995-06-07 | 1997-07-01 | Mars Incorporated | Health food product and its uses |
| US5854015A (en) | 1995-10-31 | 1998-12-29 | Applied Food Biotechnology, Inc. | Method of making pure 3R-3'R stereoisomer of zeaxanthin for human ingestion |
| US5705624A (en) | 1995-12-27 | 1998-01-06 | Fitzmaurice; Wayne Paul | DNA sequences encoding enzymes useful in phytoene biosynthesis |
| RU2118528C1 (en) | 1996-01-16 | 1998-09-10 | Казарян Роберт Врамович | Composition for preparing medicinal forms and foodstuffs enriching |
| US20040191297A1 (en) * | 1997-05-22 | 2004-09-30 | Lance Schlipalius | Carotenoid formulation |
| AUPO693397A0 (en) | 1997-05-22 | 1997-06-12 | Betatene Limited | Carotenoid formulation |
| WO1998057622A1 (en) | 1997-06-19 | 1998-12-23 | Lycored Natural Products Industries Ltd. | Synergistic compositions for lycopene and vitamin e for the prevention of ldl oxidation |
| IL123132A (en) * | 1998-02-01 | 2003-10-31 | Lycored Natural Prod Ind Ltd | Synergistic composition for preventing ldl oxidation and arresting the progression of atherosclerosis, comprising lycopene and garlic |
| IL126076A (en) * | 1998-09-04 | 2005-05-17 | Ibr Ltd | Transparent composition comprising phytoene and phytofluene |
| GB9922751D0 (en) * | 1999-09-27 | 1999-11-24 | Kenton Corp Limited | A pharmaceutical composition for stabilising atherosclerotic plaques |
| DE10036797A1 (en) | 2000-07-28 | 2002-02-07 | Beiersdorf Ag | Use of combinations containing carnitines |
| IL141039A (en) * | 2001-01-23 | 2006-10-31 | Lycored Natural Prod Ind Ltd | Anti-atherosclerosis composition containing carotenoids and use in the preparation of medicaments for inhibiting ldl oxidation |
| IL141038A (en) | 2001-01-23 | 2006-10-05 | Lycored Natural Prod Ind Ltd | Use of carotenoids in the preparation of anti-hypertension agents |
| IL146496A0 (en) | 2001-11-14 | 2002-07-25 | Lycored Natural Prod Ind Ltd | Carotenoid composition and method for protecting skin |
-
2001
- 2001-01-23 IL IL141039A patent/IL141039A/en active IP Right Grant
-
2002
- 2002-01-21 JP JP2002559016A patent/JP4405151B2/en not_active Expired - Fee Related
- 2002-01-21 ES ES02716282T patent/ES2346047T3/en not_active Expired - Lifetime
- 2002-01-21 AU AU2002226652A patent/AU2002226652B2/en not_active Expired
- 2002-01-21 WO PCT/IL2002/000053 patent/WO2002058682A2/en active Application Filing
- 2002-01-21 PL PL361734A patent/PL208263B1/en unknown
- 2002-01-21 CA CA002435613A patent/CA2435613C/en not_active Expired - Fee Related
- 2002-01-21 CN CNB028070461A patent/CN1273119C/en not_active Expired - Fee Related
- 2002-01-21 US US10/466,957 patent/US7351746B2/en not_active Expired - Lifetime
- 2002-01-21 AT AT02716282T patent/ATE471716T1/en not_active IP Right Cessation
- 2002-01-21 EP EP02716282A patent/EP1363609B1/en not_active Expired - Lifetime
- 2002-01-21 RU RU2003122061/14A patent/RU2288707C2/en not_active IP Right Cessation
- 2002-01-21 DE DE60236787T patent/DE60236787D1/en not_active Expired - Lifetime
- 2002-01-21 BR BR0206942-3A patent/BR0206942A/en not_active Application Discontinuation
- 2002-01-21 KR KR1020037009661A patent/KR100841238B1/en active IP Right Grant
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2003
- 2003-07-17 NO NO20033232A patent/NO20033232L/en not_active Application Discontinuation
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2007
- 2007-11-16 US US11/941,881 patent/US7786175B2/en not_active Expired - Fee Related
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2009
- 2009-08-14 JP JP2009187954A patent/JP2010006816A/en active Pending
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