CA2435613C - 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 oxidation Download PDF

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Publication number
CA2435613C
CA2435613C CA002435613A CA2435613A CA2435613C CA 2435613 C CA2435613 C CA 2435613C CA 002435613 A CA002435613 A CA 002435613A CA 2435613 A CA2435613 A CA 2435613A CA 2435613 C CA2435613 C CA 2435613C
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Prior art keywords
phytoene
phytofluene
ldl
oxidation
mixtures
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Expired - Fee Related
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CA002435613A
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French (fr)
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CA2435613A1 (en
Inventor
Morris Zelkha
Tanya Sedlov
Zohar Nir
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Lycored Ltd
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Lycored Natural Products Industries Ltd
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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
    • A61K31/01—Hydrocarbons
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Abstract

An anti-atherosclerosis composition comprising a LDL-oxidation inhibiting effective amount of phytoene, phytofluene or mixtures thereof and a method f or inhibiting the progression of atherosclerosis.

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., Free 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-oxidation, 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, phytofluehe or mixtures thereof, for inhibiting the oxidation of LDL.

A fizrther 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.

-2a-According to one aspect of the present invention, there is provided use of an effective anti-LDL-oxidation amount of phytoene, phytofluene or mixtures thereof, in the manufacture of a medicament for inhibiting the progression of atherosclerosis.

According to another aspect of the present invention, there is provided an anti-atherosclerosis composition comprising an LDL-oxidation inhibiting effective amount of at least 0.1 mg of phytoene, phytofluene or mixtures thereof, and a pharmaceutically acceptable adjuvant, excipient or additive.

According to still another aspect of the present invention, there is provided use of a composition comprising at least 0.1 mg of phytoene, phytofluene or mixtures thereof, for inhibiting the oxidation of LDL.

According to yet another aspect of the present invention, there is provided use of phytoene, phytofluene or mixtures thereof, in the preparation of a medicament for inhibiting the oxidation of LDL and the progression of atherosclerosis.

According to a further aspect of the present invention, there is provided use of an anti-LDL-oxidation effective amount of phytoene, phytofluene or mixtures thereof in the preparation of dietary supplements, food stuff and drinks.

According to yet a further aspect of the present invention, there is provided a composition as described herein, for use in inhibiting the progression of atherosclerosis.
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 androf 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, (3-carotene, and phytofluene/phytoene on LDL
oxidation.

Fig. 4 (A),(B) - Effect of lycoepene in combination with antioxidants on LDL
oxidation.
Fig. 5 (A),(B) - Effect of (3-Carotene in combination with antioxidants on LDL
oxidation.
Fig. 6 (A),(B) - Effect of vitamin E in combination with antioxidants on LDL
oxidation.
Fig. 7 (A),(B) - Effect of phytofluene/phytoene in combination with antioxidants on LDL oxidation.
.15 Fig. 8 (A),(B) - Effect of combination of antioxidants 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 M.
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 1 mg/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 (100 g 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 5 M of CuSO4, for 2 hours at 37 C. LDL oxidation was terminated by adding 1mM 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 lyconene and of tomato oleoresin on conner ion-induced LDL oxidation: Concentration study.

LDL (100 g 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 mol/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 l A) and in lipid peroxides (Fig 1 B) formation, respectively, was obtained on using 50 mol/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 mol/L and 8.4 mol/L of lycopene equivalents for the inhibition of TBARS (Fig 1 A) and of lipid peroxides.(Fig 1B) formation, respectively.
Example 2: Effect of phytofluene/phytoene on copper ion-induced LDL oxidation:
Concentration study.

Phytofluene/phytoene dose-dependently inhibited CuSO4-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 g/ml for inhibition of TBARS formation and 0.35 g/ml for inhibition of lipid peroxides formation, respectively.

Example 3: Effect of lycopene, vitamin E, R-carotene, and phytofluene/phytoene on LDL oxidation.

At the low concentration, which mimics the composition of Lyc-O-Mato , Lycopene (l0 g/ml), vitamin E(2.5 g/ml) and (3-carotene (0.4 g/ml) did not significantly affect LDL oxidation. In contrast, phytofluene/phytoene (1.2 g/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 g/ml) in combination with each one of the other antioxidants separately (2 compound in each study), the addition to lycopene to (3-carotene (0.4 g/ml) or vitamin E(2.5 g/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 (1.2 g/ml) inhibited LDL oxidation by as much as 95%.
These results, presented in Fig. 4 show that the addition to lycopene of P-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

rv.~.9~..,_.
oxidation (alone, and in combination with lycopene). Similar results were obtained for LDL oxidation analysis by the lipid peroxides assay.

Example 5: Effect of R-Carotene in combination with antioxidants on LDL
oxidation.

With reference to Fig. 5, on using (3-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 (3-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 P-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 0-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 nhytofluene/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, (3-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-Mato was compared to a mixture of carotenoids prepared from the combination of 5 antioxidant compounds in the following concentrations;
lycopene (lOpg/ml), 0-carotene (0.4 g/ml), Vitamin E(2.5 g/ml) and phytoene/phytofluene (1.2 g/ml). 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 (24)

CLAIMS:
1. Use of an effective anti-LDL-oxidation amount of phytoene, phytofluene or mixtures thereof, in the manufacture of a medicament for inhibiting the progression of atherosclerosis.
2. Use of an effective anti-LDL-oxidation amount of phytoene, phytofluene or mixtures thereof, for inhibiting the progression of atherosclerosis.
3. A use according to claim 1 or 2 wherein the phytoene, phytofluene or mixtures thereof are adapted for administration to a subject in need thereof in an amount of at least 0.2 mg/day.
4. A use according to any one of claims 1 to 3 wherein a mixture of phytoene and phytofluene is used.
5. A use according to claim 3 wherein the ratio of phytoene and phytofluene in the mixture is from about 1:20 to about 20:1.
6. A use according to any one of claims 1 to 5 wherein administration is in a daily dose.
7. A use according to any one of claims 1 to 6 wherein the phytoene, phytofluene or mixtures thereof, are used in conjunction with another anti-atherosclerosis agent.
8. A use according to any one of claims 1 to 7 wherein administration is adapted 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.
9. An anti-atherosclerosis composition comprising an LDL-oxidation inhibiting effective amount of at least 0.1 mg of phytoene, phytofluene or mixtures thereof, and a pharmaceutically acceptable adjuvant, excipient or additive.
10. A composition according to claim 9 comprising at least 0.1 mg of phytoene, and a pharmaceutically acceptable adjuvant, excipient or additive.
11. A composition according to claim 9 comprising 0.1 mg phytofluene, and a pharmaceutically acceptable adjuvant, excipient or additive.
12. A composition according to claim 9 comprising at least 0.1 mg of a mixture of phytoene and phytofluene.
13. A composition according to claim 12 wherein the ratio of phytoene and phytofluene in the mixture is from about 1:20 to about 20:1.
14. A composition according to claim 9 comprising at least 0.1 mg of phytoene, phytofluene or mixtures thereof, and a pharmaceutically acceptable adjuvant, excipient or additive in the form of a solid dosage tablet, capsule, hard-shell capsule, soft gel or gelcap.
15. Use of a composition comprising at least 0.1 mg of phytoene, phytofluene or mixtures thereof, for inhibiting the oxidation of LDL.
16. Use of a composition according to claim 15 in conjunction with another 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 at least 0.1 mg of phytoene.
19. Use according to claim 17 wherein the medicament comprises at least 0.1 mg of phytofluene.
20. Use according to claim 17 wherein the medicament comprises at least 0.1 mg of a mixture of phytoene and phytofluene.
21. Use according to claim 20 wherein the ratio of phytoene and phytofluene in the mixture is from about 1:20 to about 20:1.
22. Use of an anti-LDL-oxidation effective amount of phytoene, phytofluene or mixtures thereof in the preparation of dietary supplements, food stuff and drinks.
23. Use according to claim 22 wherein about 0.1 mg of phytoene, phytofluene or mixtures thereof is added to the dietary supplements, food stuff and drinks.
24. A composition according to any one of claims 9 to 14, for use in inhibiting the progression of atherosclerosis.
CA002435613A 2001-01-23 2002-01-21 An anti-atherosclerosis composition containing carotenoids and method for inhibiting ldl oxidation Expired - Fee Related CA2435613C (en)

Applications Claiming Priority (3)

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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

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CA2435613C true CA2435613C (en) 2008-11-18

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JP (2) JP4405151B2 (en)
KR (1) KR100841238B1 (en)
CN (1) CN1273119C (en)
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IL (1) IL141039A (en)
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US7786175B2 (en) 2010-08-31
EP1363609A2 (en) 2003-11-26
NO20033232D0 (en) 2003-07-17
JP2010006816A (en) 2010-01-14
RU2288707C2 (en) 2006-12-10
US20040110849A1 (en) 2004-06-10
CA2435613A1 (en) 2002-08-01
AU2002226652B2 (en) 2006-09-07
KR100841238B1 (en) 2008-06-25
US20080114074A1 (en) 2008-05-15
ATE471716T1 (en) 2010-07-15
ES2346047T3 (en) 2010-10-08
CN1273119C (en) 2006-09-06
JP4405151B2 (en) 2010-01-27
PL361734A1 (en) 2004-10-04
IL141039A0 (en) 2002-02-10
CN1498102A (en) 2004-05-19
KR20030091972A (en) 2003-12-03
DE60236787D1 (en) 2010-08-05
IL141039A (en) 2006-10-31
EP1363609B1 (en) 2010-06-23
NO20033232L (en) 2003-09-22
JP2004520373A (en) 2004-07-08
BR0206942A (en) 2004-02-25
WO2002058682A3 (en) 2003-01-03
PL208263B1 (en) 2011-04-29
WO2002058682A2 (en) 2002-08-01
US7351746B2 (en) 2008-04-01

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