RU2242220C2 - Pharmaceutical or dietetic composition for reducing mammal blood igf-i level and method for reducing igf-i level - Google Patents

Abstract

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to pharmaceutical or dietetic composition for reducing level of IGF-I in mammal blood that involves effective amount of carotinoid lycopene reducing the level of IGF-I. Also, invention provides reducing levels of IGF-I that involves administration in subject of lycopene in effective dose, if necessary, and reducing the level of IGF-I. The advantage of invention involves the development of preparation reducing the level of IGF-I in mammal blood effectively.

EFFECT: valuable properties of composition.

14 cl, 1 dwg, 1 ex

Description

This invention relates to pharmaceutical and dietary compositions comprising a combination of compounds useful in preventing cancer, and to the use of said compositions and said combination of compounds for the indicated purpose. More specifically, this invention relates to a pharmaceutical or dietary composition for reducing plasma levels of insulin-like growth factor-I (IGF-I) in mammals.

It has been found that IGF-I levels are a major risk factor for prostate cancer (Chan JM, Stampfer MJ, Giovannucci E., Gann PH, Winkinson P., Hannekens CH and Pollak M. "Insulin-like growth factor-I in plasma and danger Prostate cancer: The upcoming study "(" Plasma insulin-like growth factor-I and prostate cancer risk: A prospective study "), Science. 279: 563-566, 1998) and breast cancer (Hankinson SE, Willett WC, Colditz GA , Hunter DJ, Michaud DS, Deroo B., Rosner B., Speizer FE, and Pollak M. “Circulating concentrations of insulin-like growth factor-I and risk in the bloodstream of breast cancer” of breast cancer "), Lancet. 351: 1396-1397, 1988). It is believed that the level of this growth factor in the bloodstream of a person is directly related to the risk of these and other malignant tumors. Carotenoids, which are colored pigments with lipophilic properties, are widespread in fruits and vegetables (for example, β-carotene in carrots and lycopene in tomatoes) and are active in preventing exposure to IGF-I (Unpublished results). Carotenoids move inside the bloodstream lipoproteins when they are digested in the human body.

As shown in previous epidemiological studies, carotenoid consumption is accompanied by a decrease in cancer-related mortality, although recent data do not show similar beneficial effects (see, for example: Hennekens CH, Buring JE, Manson JE, Stampfer M., Rosier B., Cook NR, Belanger C., LaMotte F., Gaziano JM, Ridker PM, Willet W. and Peto R. "Lack of effect of long-term beta-carotene supplementation in case of malignant neoplasms and cardiovascular disease" term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascula r disease "(N. Engl. J. Med. 1996; 334: 1145-1149).

Evidence regarding the ability of β-carotene supplements to protect against cancer in vitro or in vivo is controversial: some studies find the inhibitory effect of β-carotene supplements, while some others do not.

Lycopene, an open-chain analog of β-carotene, has a similar structure to it, including extended conjugated double bonds. In human blood plasma, lycopene and β-carotene are quantitatively the main carotenoids. As shown, lycopene has the greatest ability to quench singlet oxygen among various carotenoids (DiMascio P., Kaiser S. and Sies H. "Lycopene as the most effective biological carotenoid quencher of singlet oxygen"("Lycopene as the most efficient biological carotenoid singlet oxygen quencher" ), Arch. Biochem. Biophys., 1989, 274: 532-538) and it was shown that it is at least twice as effective as an antioxidant compared to β-carotene in protecting blood lymphocytes from damage by NO ₂ radical (Bohm F., Tinkler JH and Troscott TG "Carotenoid cell membrane protection against p Nitrogen Dioxide stated failures radical "(" Carotenoids protect against cell membrane damage by the nitrogen dioxide radical "), Nature Medicine, 1995, 2: 98-99).

It has been shown that lycopene significantly reduces IGF-induced tyrosine phosphorylation of the insulin receptor substrate-I and decreases the upregulation of the binding ability of the AP-I transcription complex (Karas et al. 2000. Nutr, Cancer 36 (1): 101-111). However, it has not yet been shown that lycopene causes a decrease in plasma IGF-I levels.

The aim of this invention is to provide a pharmaceutical or dietary composition or preparation that is effective in reducing plasma IGF-I levels with concomitant beneficial effects.

The aim of this invention is also the creation of such a composition or preparation, which includes products that are acceptable and desirable components of a human diet.

Another objective of the present invention is to provide a method for reducing plasma IGF-I levels in a mammal in need of such a reduction.

SUMMARY OF THE INVENTION

The objectives are achieved in that, according to the invention, the claimed pharmaceutical or diet composition for reducing the level of IGF-I in the blood of mammals includes an effective amount of lycopene to reduce the level of IGF-I.

The inventive composition as lycopene may contain lycopene from tomatoes, natural resin from tomatoes or synthetic lycopene.

A unit dose of said composition preferably includes at least about 3 mg of lycopene.

The specified composition may contain compounds selected from the group including dietary components, additives, excipients, binders, coatings, preservatives and mixtures thereof.

The specified composition can be applied in the form of dosage forms selected from the group comprising tablets, coated tablets, capsules with herbal supplements and capsules with hard gelatin shells.

The present invention is based on the discovery that there is an unexpected and surprising decrease in plasma levels of insulin-like growth factor-I (IGF-I) after the addition of lycopene to a mammalian organism.

In addition, the present invention provides a method for reducing plasma levels of IGF-I in a mammal, wherein said method comprises administering to the mammal, if necessary, an IGF-I reducing effective amount of lycopene. As lycopene can be used lycopene from tomatoes, natural resin from tomatoes or synthetic lycopene. The unit dose of lycopene administered is at least about 3 mg.

DETAILED DESCRIPTION OF THE INVENTION

The description provided is an illustration of preferred embodiments of the invention. The proposed description should not be construed as limiting, it should be understood that specialists in this field can perform many obvious variants of the invention.

The invention includes a method for decreasing the level of IGF-I in blood plasma, which comprises administering lycopene to the patient in an amount of at least 3 mg per day.

Lycopene, which is a natural product and is present in tomatoes in various concentrations, but which can also be produced synthetically, synthetic lycopene, compositions including it and their use are included in the present invention. The composition may contain other dietary components, additives, excipients, binders, coatings, etc., or other compounds that do not have a significant effect on the reduction of IGF-I. The compositions according to the invention, from the point of view of their purpose, are a pharmaceutical composition. However, since their components are individually acceptable ingredients of the human diet and, in fact, are individually present in food products, they can be considered and used as diet or health improving compositions.

A natural tomato resin includes a combination of lycopene with vitamin E, β-carotene, phytoene and phytofluene, and therefore, the use of a natural tomato resin to lower levels of insulin-like growth factor-I in blood plasma is a specific aspect of the present invention. Both natural tomato resins and pure lycopene reduce plasma IGF-I levels by at least 10% in tested patients.

In a preferred embodiment of the invention and in the examples to be described, lycopene was obtained from a natural resin from tomatoes. Natural tomato resin was supplied by LycoRed Natural Products Industries, Ltd., Beer Sheva, Israel. It contained crystalline lycopene (5%) suspended in the lipid phase of a tomato.

Fatty acids, such as triglycerides, made up the bulk (72%) of the natural resin, while 19% were unsaponifiables, including, among other things, 5% lycopene, 0.1% β-carotene, 1% vitamin E, and phytoen and phytofluen. The lycopene used was extracted and purified, mainly in a configuration that was completely transconfiguration. Lycopene can be extracted from a natural tomato resin by a crystallization method known in the art, followed by filtration.

Said composition can be prepared according to conventional methods well known in the art when lycopene is added to the composition.

Examples

Example 1: Exposure to a Natural Resin Additive from Tomato Plasma IGF-I Levels

The effect of lycopene supplementation on IGF-I levels in the blood of patients undergoing selective hemorrhoidectomy was studied. Lycopene was administered (5% in a natural tomato resin, two 15 mg capsules per day) or placebo for three to four weeks before surgery. The concentration of lycopene and the distribution of isomer in the blood and in the removed tissues was measured using high-resolution liquid chromatography by HPLC. Blood lycopene levels decreased in most subjects who received lycopene supplementation. In the placebo group, the level of lycopene in the blood plasma before administration was similar to the level of lycopene in the group that was exposed to lycopene, and did not change significantly after the addition. IGF-I levels were measured using an IRMA kit (DSL-5600 Active. Diagnostic System Laboratories, Webster, TX). Baseline plasma IGF-I levels varied significantly among subjects. In 15 of 28 patients in the group exposed to lycopene (53%), the level of IGF-I in the blood decreased by more than 10%. In 7 patients (25%), no changes were observed. In contrast, only 4 out of 28 patients who were exposed to placebo (14%) showed a decrease in plasma IGF-I, and 20 patients (71%) did not show any changes. These data clearly show that lycopene supplementation is effective in significantly lowering IGF-I levels in a specific portion of subjects that are “responders”. In contrast, when the effects of lycopene supplementation on blood levels of IGF-II and IGF-BP-3 were tested, no differences were found between the group exposed to lycopene and the group exposed to placebo. IGF-I was measured using ELIZA (DSL-10-91000), and IGF-BP-3 was measured using IRMA (DSL-6600) using kits from Diagnostic System Laboratories, Webster, TX.

Example 2

We measured the absorption of dietary lycopene and the effect of this supplement on blood IGF-I levels in patients undergoing cancer-related surgery:

- Lycopene tomato (30 mg / day) or placebo was administered orally for several days (4-7) before surgery.

- The concentration of lycopene in the blood was measured using HPLC (high performance liquid chromatography).

- IGF-I, -IGF-II and IGFBP-3 in the blood were measured using routine laboratory tests.

Objects and treatment

The study was carried out using a double-blind statistical method by comparing a group of patients who took extraction tomato essential oil during treatment with a group of patients taking placebo. Volunteers (in the amount of 40 people), candidates for surgery related to colon cancer, were recruited from the local community about a week before the operation during the period from November 1998 to October 2000. The participation of patients in the study did not contradict their treatment plans and did not affect the time between diagnosis and surgery, which was determined solely by the clinical conditions. The study was approved by the local medical ethics committee and the Israeli Ministry of Health. Patients were asked to sign an agreement based on the information received before the study began, and they were statistically divided into a group of patients who would take lycopene and a group of patients who would take a placebo. Information regarding BMI, health status, and medical conditions was obtained from patients and from medical records. The demographic characteristics of the two groups of patients were similar and there were no differences between the groups of patients that could affect the results of the study.

Volunteers were given lycopene supplements from a natural source or placebo for a varying period of time before surgery (depending on the time between seeking help and surgery). Lycopene was administered as a tomato extraction essential oil (LYC-O-MATO®; LycoRed Natural Products Industries Ltd, Beer-Sheva, Israel), which is made from proprietary tomato products rich in lycopene and made in the form of soft gel capsules. Each capsule contains 15 mg of lycopene and about 1.5 mg of phytoene, 1.4 mg of phytofluene, 0.4 mg of β-carotene and 5 mg of tocopherols. The placebo contained refined soybean oil instead of the tomato essential oil component. Patients were asked to take one capsule twice daily (30 mg of lycopene / day) with food and not change their constant diet.

Two blood samples were obtained for analysis (before and after treatment). Serum samples were stored at -70 ° C. The medical purpose of blood and tissue samples was hidden from medical and laboratory personnel.

results

Lycomato supplementation caused an almost twofold increase in serum lycopene levels. Interestingly, a small, slight increase in serum lycopene levels was observed in patients taking placebo (Figure 1).

Lycomato supplementation caused a significant (29%) drop in serum IGF-I level with a slight change that was observed in placebo-treated patients.

IGF-II and BP-3 levels did not change (not shown) in most cases. In some cases, the rise or fall of the level did not differ between the group of patients taking the lycopene supplement and the group of patients taking the placebo.

Conclusion

Supplementing tomato extract can reduce the risk of cancer by lowering serum IGF-I levels.

While the variants of the invention and experimental data have been characterized by illustration, it should be understood that the invention is not limited to this and can be carried out with many modifications, variations and adaptations, without departing from the essence or without going beyond the scope of the claims.

Claims (14)

1. A pharmaceutical or diet composition for reducing the level of IGF-I in mammalian blood, which comprises an effective amount of lycopene to reduce the level of IGF-I. 2. The composition according to claim 1, characterized in that it includes lycopene from tomatoes. 3. The composition according to claim 1, characterized in that it includes a natural resin from tomatoes. 4. The composition according to claim 1, characterized in that it includes synthetic lycopene. 5. The composition according to claim 1, characterized in that the standard dose of the specified composition includes at least about 3 mg of lycopene. 6. The composition according to any one of claims 1 to 5, characterized in that it contains compounds selected from the group including dietary components, additives, excipients, binders, coatings, preservatives, and mixtures thereof. 7. The composition according to any one of claims 1 to 6, in the form of dosage forms selected from the group comprising tablets, coated tablets, capsules with herbal additives and capsules with hard gelatin shells. 8. A method of reducing the level of IGF-I in the blood of mammals, if necessary, comprising introducing the specified mammal an effective amount of lycopene. 9. The method of claim 8, wherein said lycopene is a tomato lycopene. 10. The method according to claim 8, characterized in that said lycopene is a synthetic lycopene. 11. The method according to claim 8, characterized in that said lycopene is a natural resin from tomatoes. 12. The method according to claim 8, characterized in that the standard dose of lycopene administered is at least about 3 mg. 13. The method according to any one of paragraphs.8-12, characterized in that lycopene is administered in the form of a composition comprising dietary components, additives, excipients, binders, coatings, preservatives and mixtures thereof. 14. The method according to any one of claims 8 to 13, characterized in that the composition is administered in dosage forms selected from the group consisting of tablets, coated tablets, capsules with herbal additives, and hard gelatin capsules.