HK1039062A1

HK1039062A1 - Antioxidant, antiproliferous composition, comprising a carnitine and a carotenoid

Info

Publication number: HK1039062A1
Application number: HK02100334.3A
Authority: HK
Inventors: C‧卡瓦扎
Original assignee: 希格马托保健科学股份公司; 希格馬托保健科學股份公司
Priority date: 1998-08-03
Filing date: 1999-07-29
Publication date: 2002-04-12
Also published as: SK1252001A3; WO2000007581A2; IL140797A0; AU5064199A; EE200100052A; WO2000007581A3; NO20010532L; IT1302125B1; HUP0102807A2; NO20010532D0; TNSN99152A1; BR9912703A; CA2338035A1; ITRM980516A1; IS5816A; ITRM980516A0; AR021172A1; KR20010072146A; TR200100333T2; PL346161A1

Abstract

A composition is disclosed which comprises as characterizing active ingredients propionyl L-carnitine and at least one carotenoid, typically the lycopene extracted from tomato for the prevention and/or therapeutic treatment of various alterations and pathological states induced by free radicals and by lipoperoxidation phenomena, that may take the form of a idetary supplement, dietetic support or of an actual medicine.

Description

Antioxidant and antiproliferative composition containing carnitine and carotenoid

no marking

The present invention relates to a composition useful for preventing and/or treating diseases caused by the presence of free radicals resulting from environmental pollution and lipid peroxidation of atherosclerosis, blood vessels, heart or brain; tissue proliferation including prostate, uterine, breast or colon tissue; a composition of vision and retina comprising cataracts and macular degeneration of the retina.

Thus, depending on the intended feeding or prophylactic effect or strictly therapeutic effect of the composition on the particular subject in use, the composition may take the form of and function as a food supplement or medicament.

More particularly, the invention relates to a composition that can be administered orally, parenterally, rectally, transdermally or by ocular instillation, comprising in combination:

(a) propionyl L-carnitine or a pharmaceutically acceptable salt thereof, in combination with other "carnitine", where "carnitine" refers to L-carnitine or an alkanoyl L-carnitine selected from acetyl L-carnitine, valeryl L-carnitine and isovaleryl L-carnitine or their pharmaceutically acceptable salts; and

(b) the carotenoid is preferably an extract selected from lycopene, alpha-carotene, beta-carotene, zeaxanthin, cryptoxanthin, lutein or mixtures thereof or natural vegetable products containing carotenoids, typically tomato extract (Lycopersicon esculentum).

Carotenoids are a group of long-chain plant pigments with a conjugated system of double bonds, containing up to 40 carbon atoms, having terpene-like properties (tetraterpenes). Carotenoids are present in higher plants, chloroplasts, and in those plastids located in regions of plants lacking chlorophyll (certain roots and many flowers and fruits, such as tomato, where carotenoids are increased during maturity); carotenoids are also found in blue algae, certain photosynthetic bacteria, and certain fungi. During photosynthesis, carotenoids play a role in chlorophyll supplementation, absorbing some light and transmitting energy to chlorophyll itself.

Although there are over 600 carotenoids in the plant world, there are only 40 in the human diet, only 14 that can be absorbed by the internal organs, the remainder being made up of non-absorbing epoxides. The most common of these 14 are lycopene, alpha-carotene, beta-carotene, lutein, zeaxanthin, and beta-cryptoxanthin.

Lycopene has 11 (9) linear conjugated double bonds (among which beta-carotene is present), and is a carotenoid with the longest chain among the linear conjugated double bonds.

The relationship between this particular structure and its greater ability to act as an antioxidant has been required.

Despite the metabolic interaction between lycopene and beta-carotene, lycopene cannot convert itself in vivo to beta-carotene, which is characterized by a trimethylcyclohexane ring on either side of the carbon chain.

On the other hand, β -carotene can convert itself to trans-retinol and retinoic acid by chain reduction and has a provitamin a-like effect.

These compounds have substantial antioxidant capacity, but among them lycopene has the maximum blocking capacity for singlet oxygen, which is more than twice as much as that of, for example, beta-carotene.

Lycopene is absorbed by the human body, particularly in the presence of fat, and can be found in two forms, cis-and trans-lycopene, in blood and fat.

Like all carotenoids, lycopene cannot be synthesized by the body and must be taken by the diet.

There are many foods containing carotenoids including papaya, grapefruit powder, spinach, apricot, milk and egg, but all of them contain the greatest amount of lycopene than tomato.

In addition to their substantial antioxidant capacity, lycopene is of interest as a result of epidemiological studies which show that carotenoids with provitamin a-like effects, such as β -carotene, can themselves protect some forms of tumours without the need for conversion to the retinol form. Some prospective and retrospective findings indicate an inverse correlation between carotene consumption in carotene-rich vegetables and fruits or high plasma concentrations and tumor risk (especially lung tumors). These results are attributed to the carotenoid, simply because it is a precursor of vitamin a. However, recent clinical trials have again shown that the use of β -carotene alone in the diet has no beneficial effect on the risk of tumor risk compared to a large population lacking this vitamin in the diet.

The same negative results were obtained in the group of smokers or in the group of individuals at risk of asbestos lung. After processing these data, it was again found that carotenoids other than beta-carotene contributed to obtaining protection detectable by other experiments.

The basis for characterizing lycopene and making it believed that it can act as a beneficial organism in vivo is that it has a strong antioxidant effect, most notably an anti-singlet oxygen effect, which is one of the most active oxygen products in the production of free radicals. In addition to its effect against singlet oxygen, lycopene is extremely active in protecting cells and tissues from damage by other reactive species of oxygen (e.g., hydrogen peroxide and nitrous oxide).

Some of the reasons that lycopene may play a beneficial health-promoting role with dietary intake are these specific activities of lycopene, which are what makes it prominent among all other natural antioxidants.

In fact, it has now been found that patients suffering from myocardial infarction and those potentially at risk of having higher blood concentrations of cholesterol or triglycerides show very low blood concentrations of beta-carotene, in particular lycopene, compared to the control group. The above-mentioned phenomena, which are related to the anti-lipid peroxidation of lycopene, are also revealed from studies demonstrating that lycopene is present in LDLs and can prevent its oxidation.

It has been shown that lycopene also has superior lipid peroxidation resistance to beta-and alpha-carotene when assayed in cell culture (C3H/10T1/2 cells), where it prevents their neoplastic transformation. The anti-lipid peroxidation of lycopene also explains its ability to prevent atherosclerosis and atherosclerotic vascular injury, and is also associated with its intracellular communication enhancing activity of immunoglobulin inhibition and binding and tumor cell proliferation.

Lycopene is the most potent carotenoid in inhibiting the spontaneous development of mammary tumors in rats and the growth of leukemia cells (H1-60 promyelocytic leukemia cell line) and rat glioma C-6 cells in vitro or transformation of tumor formation induced by chemical agents.

Epidemiological studies have demonstrated an inverse relationship between lycopene intake with diet and the risk of developing prostate tumors, and thus lycopene may be used as a prophylactic in this particular disease. The same is true of the risk of breast and lung tumors.

Another disease in which lycopene, such as lutein, zeaxanthin, may exert a protective effect is age-related macular degeneration (AMD).

The important roles of L-carnitine and its alkanoyl derivatives are well known and they can play a role at the metabolic level, especially for oxidation and fatty acid utilization by beta-oxidation.

In fact, L-carnitine, whether taken from the diet or synthesized by the body, is concentrated in the blood in organs where they are very active in the metabolism of fatty acid utilization, such as in skeletal muscle and heart.

L-carnitine deficiency can lead to myopathy, while oral administration of L-carnitine can improve the clinical condition of such myopathy. L-carnitine also plays an important role in energy production in the mitochondrial oxidation of glucose, as a result of which a sufficient level of L-carnitine is required for normal energy metabolism at the myocardial and muscular level.

Administration of L-carnitine may improve stress tolerance, coronary blood flow itself and clinical symptoms of cardiac decompensation in patients with coronary insufficiency.

Other biological properties of L-carnitine and its derivatives, especially of propionyl-phytin, are its ability to stabilize cell membranes and its ability to protect cells from damage due to oxidative processes.

Surprisingly, compositions have now been found which contain the following combination of characteristics: (a) propionyl L-carnitine or a pharmaceutically acceptable salt thereof, and (b) a compound selected from the group consisting of lycopene, alpha-carotene, beta-carotene, zeaxanthin, cryptoxanthin,

lutein or mixtures thereof. Is extremely effective in preventing and/or treating the following diseases: diseases caused by the presence of free radicals due to environmental pollution and lipid peroxidation of atherosclerosis, blood vessels, heart or brain; proliferative disorders of tissue include prostate, uterine, breast or colon tissue; vision and retinal disorders including cataracts and macular degeneration of the retina, because these components have potent synergistic effects.

It has now been found that component (a) may further preferably comprise a "carnitine" selected from the group consisting of: l-carnitine, acetyl L-carnitine, valeryl L-carnitine and isovaleryl L-carnitine or their pharmaceutically acceptable salts or mixtures thereof, and component (b) may consist of an extract of a plant product containing it, such as tomato (Lycopersicon esculentum, Solanaceae family) extract.

(a) The weight ratio of (a) to (b) is 1: 0.1 to 1: 10.

Toxicology experiments

Both carnitine and its derivatives and lycopene and other carotenoids (e.g. lutein, zeaxanthin, cryptoxanthin, and beta-carotene) are less toxic and are better tolerated by animals, especially when administered orally.

The above advantages can be confirmed by administering orally to rats a high dose of L-carnitine (1g/Kg), or propionyl L-carnitine (1g/Kg), or L-carnitine (250mg/Kg) plus propionyl L-carnitine (250mg/Kg), plus acetyl L-carnitine (250mg/Kg) plus isovaleryl L-carnitine (250mg/Kg), and can also be confirmed by administering 50mg/Kg of lycopene or 1g/Kg of a natural tomato extract containing 5% of lycopene.

Oral administration of a composition of 1g/Kg propionyl L-carnitine and 50mg/Kg lycopene in rats also proved to be well tolerated and did not cause death in the treated animals.

Similar results were obtained with a composition of carnitine mixture (L-carnitine 250mg/Kg plus acetyl L-carnitine 250mg/Kg plus propionyl L-carnitine 250mg/Kg plus isovaleryl L-carnitine 250mg/Kg) and 50mg/Kg lycopene.

The same ideal results were obtained with a combination of propionyl L-carnitine (500mg/Kg), or a mixture of various carnitine (150 mg/Kg of L-carnitine plus acetyl L-carnitine plus 150mg/Kg of propionyl L-carnitine plus 150mg/Kg plus isovaleryl L-carnitine plus 150mg/Kg of lycopene) and 25mg/Kg of lycopene administered orally to rats daily over a longer period of time (30 days).

At the end of 30 days, the treated rats had no signs of death and toxicity. Physicochemical experiments found that the treated animals exhibited normal red and white blood cell counts, as well as histological examination of the major organs after treatment.

In vitro hepatocyte experiments poisoned by carbon tetrachloride

To evaluate the antioxidant and protective activity of the compositions of the invention on free radicals, their effect on ex vivo hepatocyte cultures detoxified with carbon tetrachloride was analyzed.

Carbon tetrachloride (CCl) is known₄) Lipid peroxidation of cell membranes can be induced, which can lead to cell necrosis.

These experiments performed in rat hepatocyte cultures demonstrate that CCl is associated with free radical release₄The lipid peroxidation and toxicity effects of (a) can be reduced by the presence in the culture of a carnitine mixture consisting of L-carnitine, acetyl L-carnitine, propionyl L-carnitine and isovaleryl L-carnitine in a weight ratio of 1: 1, and also by the presence in the culture of propionyl L-carnitine (100mg/L), especially when used in combination with lycopene (20mg/L) or a tomato extract containing 5% lycopene.

To perform these experiments, hepatocytes were isolated from rat liver using the method described by Seglen (Seglen f.o.meth.cell.biol.chem.,264,4747).

CCl can be determined by analysis of alanine aminotransferase (AlaAT) and aspartate aminotransferase (aspaAT) in the supernatant fluid of cell culture₄Induced damage to cell membranes and protection by carnitine mixtures or propionyl L-carnitine or lycopene and their combinations (Beckman 700-Encore 2 automated biochemical analysis system).

The barbituric acid method (Ohkawa H.anal.biochem.,95,351,1979) was used to treat the compounds of the invention for CCl₄The protective effect of lipid peroxidation of malonyl aldehyde was evaluated.

After the treatment, the hepatocytes were fixed under an optical and electron microscopeCytology was measured in formalin or glutaraldehyde. These experimental results show that protecting liver cells against membrane damage and CCl₄There is an unexpected synergy in the induced lipid peroxidation between the carnitine mixture and lycopene and between propionyl L-carnitine and lycopene.

The synergistic effect present between carnitine, in particular propionyl L-carnitine, and lycopene is also evident in the determination of malonyl aldehyde, an indicator of lipid peroxidation.

Cytological assays of hepatocytes confirmed: necrotic cells were reduced after treatment with propionyl L-carnitine and lycopene, however, in the superstructure assay, when the control group (CCl)₄) When cells in (1) show hemochrome abnormality, nuclear membrane irregularity, mitochondrial cristae disappearance in mitochondria and reduction in the number of ribosomes, those are not only exposed to CCl₄Furthermore, the cells exposed to carnitine and lycopene unexpectedly displayed intact cell membranes and nuclei, regular heterochromosomes, and regular hemoglobin and ribosome counts.

Normalization of the cytological appearance of hepatocytes exposed to the combined activity of the carnitine mixture and lycopene was surprisingly significant, whereas the effect of the individual compounds (not used) was not significant, thus demonstrating a significant synergistic effect between carnitine and lycopene.

TABLE 1

Alanine aminotransferase concentration suspended in hepatocyte cultures (AlaAT nmol/min) exposed to carbon tetrachloride (control) and either carnitine mixture alone or propionyl L-carnitine or natural tomato carotenoid extract or lycopene or various combinations thereof (C = carnitine mixture; P = propionyl L-carnitine; TE = natural tomato extract; L = lycopene).

Time (hr) 4816

Control 24.6. + -. 2.126.8. + -. 2.330.5. + -. 4.5

C 20.6±3.2 21.9±3.3 26.4±2.8

P 19.4±2.1 22.3±3.1 25.7±3.7

TE 22.3±1.8 24.3±2.7 24.7±2.9

L 22.1±2.1 20.6±2.4 23.6±2.1

C+TE 11.9±1.9 8.6±1.1 5.1±1.7

C+L 12.2±1.8 10.5±1.5 5.4±1.9

P+L 11.5±2.1 9.9±2.4 6.2±1.5

TABLE 2

Aspartate aminotransferase concentration suspended in hepatocyte cultures (AspaaT nmol/min) exposed to carbon tetrachloride (control) and either carnitine mixture alone or propionyl L-carnitine or natural tomato carotenoid extract or lycopene or various combinations thereof (C = carnitine mixture; P = propionyl L-carnitine; TE = natural tomato extract; L = lycopene).

Time (hr) 4816

Control 8.5. + -. 0.610.9. + -. 1.112.1. + -. 1.5

C 8.1±0.9 9.9±0.8 9.8±1.1

P 8.9±0.9 9.2±1.2 9.1±1.7

TE 8.2±0.8 9.1±0.9 9.0±1.2

L 8.8±1.8 8.9±0.9 9.0±1.2

C+TE 5.4±0.7 3.2±0.9 3.0±0.5

C+L 5.6±1.1 3.1±0.8 3.5±1.2

P+L 5.5±0.9 3.5±1.2 3.2±0.8

Experimentally induced cataract experiments

Among the factors associated with ocular cataracts, based on their pathogenic importance and the dysfunction of the retinal blood supply, reference was made not only to impaired glucose metabolism, but also to peroxidation of free radicals and lipid lipids, and we therefore experimentally induced the development of ocular cataracts in rats using the galactose-rich diet described by Gabbay (Gabbay k.h., n.engl.j.med.,288,831,1973).

After 8 days of treatment, rats were obtained with lenticular opacification and were classified in increasing order of severity into grades i, ii and iii according to the method described by Sippel (Sippel t. o., invest. ophthamol.,5,568,1966). These results obtained demonstrate that administration of a carnitine mixture (oral, 400mg/Kg, a combination of L-carnitine, acetyl L-carnitine, propionyl L-carnitine and isovaleryl L-carnitine, in doses consistent with each other on a body weight basis) or propionyl L-carnitine (400mg/Kg) or lycopene (5mg/Kg) or a natural tomato extract containing 5% lycopene (100mg/Kg) or a combination of these products together with galactose reduces the severity of ocular damage caused by galactose. However, the concurrent administration of the carnitine mixture and lycopene composition or propionyl L-carnitine and lycopene composition to the experimentally treated rats almost completely inhibited the development of lenticular opacification during the 8 day galactose treatment period.

TABLE 3

In the body of the rats with galactosemia, a carnitine mixture, propionyl L carnitine, natural tomato carotenoid extract and lycopene were used alone or in various combinations for the inhibition experiment of lenticular opacification (20 rats were one group).

Treatment of degree of opacification of ocular lens

mg/kg (number of lenses tested)

Ⅰ Ⅱ Ⅲ

Control 01010

Carnitine mixture (400mg/kg) 0155

Propionyl L Carnitine (400mg/kg) 0128

Natural tomato carotenoid extract (100mg/kg) 884

Lycopene (5mg/kg) 6410

Carnitine mixture (400mg/kg) +

Natural tomato carotenoid extract (100mg/kg) 1280

Carnitine mixture (400mg/kg) + lycopene (5mg/kg) 1262

Propionyl L carnitine (400mg/kg) +

Natural tomato carotenoid extract (100mg/kg) 1460

Propionyl L carnitine (400mg/kg) + lycopene (5mg/kg) 1560

Experimental atherosclerosis in rabbits

In these experiments, the effect of carnitine mixtures, propionyl L carnitine, lycopene and natural tomato extracts containing 5% lycopene, used alone or in various combinations, on experimentally induced atherosclerosis in rabbits was evaluated.

This experiment was carried out using a group of New Zealand rabbits weighing 2.9kg on average, to which 0.5% (by weight) cholesterol was added to the standard diet for 30 consecutive days. The same animal received a cholesterol-rich diet daily at a dose corresponding to 400mg/Kg of a carnitine mixture (combination of L-carnitine, acetyl L-carnitine, valeryl L-carnitine and isovaleryl L-carnitine, administered in doses equal to each other by weight), or 400mg/Kg of propionyl L-carnitine, or 5mg/Kg of lycopene, or 100mg/Kg of a natural tomato extract containing 5% of lycopene, or various combinations of the same. At the end of the 30 day treatment, blood samples were taken from the central artery of each animal ear and lipoprotein analysis was performed according to the method provided by Hatch (Hatch f.t.adv.lipid res, 6,1, 1968).

The animals were sacrificed and livers were removed therefrom for analysis of total cholesterol and triglycerides, respectively, according to the methods of Dehoff and Levy [ Dehoff j.l., clin.chem.,24,433,1978; levy A., Advances in Automated Analysis (Technicon Corp.)497, Thurman, Miami 1972 ]. The aorta and heart were isolated and the presence of atherosclerotic lesions was assessed according to Klurfeld (Klurfeld d d.m., j.med.,10,35,1979) and lesions were graded i-iv according to severity.

These experimental results show that both carnitine and lycopene (to a lesser extent) are protective against the increase in cholesterol and triglycerides in rabbits on high-fat diets, but that complete protection is only obtained when they are used in combination.

In fact, animals treated with the carnitine and lycopene composition may show a degree of protection that is not achievable by the addition of the effects produced by the individual products used separately. These experimental results also demonstrate the remarkable synergy achieved by the combination of the present invention.

TABLE 4 experiments in hypercholesterolemic rabbits

Plasma lipoprotein concentration

VLDL(mg/dl) LDL(mg/dl) HDL(mg/dl)

HC 1,119±295 485±19.9 23.1±6.5

CM 755±10.9 306±15.5 28.5±5.5

TE 880±105 295±20.7 30.1±4.2

p 805±95 280±22.5 29.5±6.2

L 715±80 260±28.5 29.3±5.5

CM+TE 290±45 155±16.5 35.5±3.9

CM+L 240±25 96±9.4 31.2±29

P+TE 250±30 105±15.5 36.9±3.5

P + L220 ± 2090 ± 10.532.1 ± 3.1HC = hypercholesterolemic control CM = carnitine mixture TE = natural tomato carotenoid extract P = propionyl L-carnitine L = lycopene

TABLE 5

Detection on hypercholesterolemic rabbit liver

Concentrations of Total Cholesterol and Triglycerides

Total cholesterol triglycerides

(mg/dl) (mg/g)

HC 1,885±315 180±15.5

CM 1,420±205 155±12.7

TE 1,475±195 139±11.5

P 1,250±145 142±12.8

L 1,200±180 135±13.8

CM+TE 985±85 115±11.6

CM+L 780±98 105±11.6

P+TE 750±64 110±10.7

P + L655 ± 9090 ± 8.5HC = hypercholesterolemic control CM = carnitine mixture TE = natural tomato carotenoid extract P = propionyl L-carnitine L = lycopene

Experiment on the antiproliferative Activity evaluated with Ornithine decarboxylase

As is known, the subcutaneous administration of phorbol, herceptin, to rats can cause skin proliferation abnormalities in treated animals, which can even lead to tumorous corneal (keratotic) processes. The proliferative abnormalities are accompanied by an increase in ornithine decarboxylase activity, which is generally proportional to the severity of the injury in all cases of pathological proliferative activation. In these experiments, 0.2cc of an aqueous solution of herceptin was injected subcutaneously into the back of the plucked hairs of mice at a dose of 5. mu.g/mouse. The experimental animals received orally a carnitine mixture consisting of L-carnitine, acetyl L-carnitine, propionyl L-carnitine, isovaleryl L-carnitine (400mg/kg) alone, at doses equal to each other calculated on a weight basis, or propionyl L-carnitine (400mg/kg) alone, or a natural tomato carotenoid extract (100mg/kg, containing 5% lycopene) alone, or lycopene (5mg/kg) alone, or a mixture of carnitine and lycopene or a composition containing a lycopene extract, or propionyl L-carnitine and lycopene or a composition containing a lycopene extract, during the period of 7 days before the treatment. In another set of experiments, the products were first dispersed in dimethyl sulfoxide and then redispersed in lanolin until a carnitine mixture was obtained at a concentration of 200mg/cc, or a carotenoid extract containing 5% lycopene at a concentration of 200mg/cc was obtained, or after lycopene at a concentration of 5mg/cc, these products were applied to the skin of mice half an hour before the injection of the herceptin.

The various formulations were applied to the skin injected with the herceptin at a dose of 0.3cc, and the injection site was protected with a closure bandage.

For the ornithine decarboxylase analysis of the skin area injected with the herceptin, the above analysis was carried out 5 hours after injection, as described by O 'Brien and Nakadate (O' Brien T.G., cancer research, 35,1662,1975; Nakadate T., cancer research, 42,2841,1982). The protein concentration in the epidermal extract was determined using the Lowry method (Lowry o.h., J: biol.chem.,193,265,1951). These experimental results show that the carotenoids, either the betaine or the natural tomato extract, as well as propionyl L-carnitine alone and lycopene alone, are only marginally protective against the proliferation phenomenon and against the increase in ornithine decarboxylase activity, in contrast to these products, which when used in combination, unexpectedly show an effective protection, thus demonstrating an unexpected and unexpected synergistic effect.

TABLE 6

Ornithine decarboxylase Activity

Treatment of Ornithine decarboxylase Activity

(CO₂nmol/60 min/mg protein)

Oral administration to the skin

Control 0.05. + -. 0.0020.03. + -. 0.001

2.4 + -0.32.6 + -0.2 of fish killing bacterin

Carnitine mixture 1.92 + -0.41.75 + -0.3

Propionyl L-carnitine 1.90 + -0.21.60 + -0.1

Tomato natural extract 1.85 + -0.31.80 + -0.2

Lycopene 1.70 + -0.11.65 + -0.1

Carnitine mixture + tomato natural extract 0.35 + -0.0050.40 + -0.06

Carnitine mixture + lycopene 0.30 + -0.030.45 + -0.05

Propionyl L-carnitine + tomato natural extract 0.36 + -0.060.30 + -0.04

Propionyl L-carnitine + lycopene 0.33 + -0.050.31 + -0.03

Illustrative, non-limiting examples of the present invention are given below. 1) Carnitine mixture mg 500

(L-carnitine 125mg, acetyl L-carnitine 125mg,

propionyl L-carnitine 125mg, isovaleryl L-carnitine

125mg)

Tomato natural extract (containing 5% lycopene) mg 1002) carnitine mixture mg 300 (L-carnitine 75mg, acetyl L-carnitine 75mg,

propionyl L-carnitine 75mg, isovaleryl L-carnitine

75mg)

Natural tomato extract (containing 5% lycopene) mg 503) propionyl L-carnitine mg 500

Natural tomato extract (containing 5% lycopene) mg 1004) propionyl L-carnitine mg 250

Natural tomato extract (containing 5% lycopene) mg 505) propionyl L-carnitine mg 500

Lycopene mg 56) propionyl L-carnitine mg 250

Lycopene mg 2.57) Carnitine mixture mg 300

(L-carnitine 75mg, acetyl L-carnitine 75mg,

propionyl L-carnitine 75mg, isovaleryl L-carnitine

75mg)

Lycopene mg 58) Carnitine mixture mg 300

(L-carnitine 75mg, acetyl L-carnitine 75mg,

propionyl L-carnitine 75mg, isovaleryl L-carnitine

75mg)

Lycopene mg 2.59) Carnitine mixture mg 300

(L-carnitine 75mg, acetyl L-carnitine 75mg,

propionyl L-carnitine 75mg, isovaleryl L-carnitine

75mg)

Carotenoid complexes

(Natural extracts of tomato, grapefruit, carrot, and orange flower) mg 30010) propionyl L-carnitine mg 400

Lycopene mg 2.5

Beta-carotene mg 5

Alpha-carotene mg 2

Lutein mg 5

Zeaxanthin mg 111) propionyl L-carnitine mg 350

Lycopene mg 5

Serenoa repens (serenoa repens) mg 50

Pygeum africanum extract mg 5012) Carnitine mixture mg 300

(L-carnitine 75mg, acetyl L-carnitine 75mg,

propionyl L-carnitine 75mg, isovaleryl L-carnitine

75mg)

Natural tomato extract (containing 5% lycopene) mg 100

Serenoa repens extract mg 50

Pygeum africanum extract mg 50

Mesona chinensis Benth (Opuntiis ficus indica) extract mg 50

Zinc aminoacetate mg 50

Selenium (1-methionine selenium) microgram 50

Vitamin E mg 10

C₀Q₁₀mg 1013) Carnitine mixture mg 400

(L-carnitine 100mg, acetyl L-carnitine 100mg,

propionyl L-carnitine 100mg, isovaleryl L-carnitine

100mg)

Natural tomato extract (containing 5% lycopene) mg 100

Anthocyanin mg 50 extracted from Rubus corchorifolius L

Polyphenol mg 10 extracted from grape

Vitamin E mg 10

Selenium methionine microgram 5014) propionyl L-Carnitine mg 300

Beta-carotene mg 5

Lycopene mg 5

Lutein mg 3

Catechin mg 5

Lipoic acid mg 5

C₀Q₁₀ mg 10

Vitamin C mg 100

Vitamin PP mg 25

Vitamin B₆ mg 25

Vitamin B₁₂ μg 250

Taurine mg 100

The meaning of pharmaceutically acceptable salts of L-carnitine or alkanoyl L-carnitine refers to any salt of these active ingredients with an acid which does not produce undesirable toxicity or side effects. These acids are well known to pharmaceutical experts.

Non-limiting examples of suitable salts are as follows: a chloride; bromide; an iodide; aspartate, acidic aspartate; citrate, acid citrate; a tartrate salt; phosphates, acidic phosphates; fumarate, acid fumarate; glycerol phosphate; glucose phosphate; a lactate salt; a maleate salt; an acidic maleate salt; orotate salts; an acidic oxalate salt; sulfates, acidic sulfates; trichloroacetate salt; trifluoroacetate and methanesulfonate.

The list of FDA-approved pharmaceutical salts is given in int.J.of pharm.38, (1986), 201-217; this recent publication is incorporated by reference.

The composition of the present invention further comprises vitamins, isoenzymes, minerals and antioxidants. Suitable excipients for the preparation of compositions for administration by a particular route will be apparent to the expert in the pharmaceutical and food industries.

Claims

1. A composition, comprising:

(a) propionyl L-carnitine or a pharmacologically acceptable salt thereof; and

(b) a carotenoid.

2. The composition of claim 1 wherein component (a) further comprises a "carnitine" selected from the group consisting of: l-carnitine, acetyl L-carnitine, valeryl L-carnitine, isovaleryl L-carnitine or their pharmaceutically acceptable salts or their mixture.

3. A composition as claimed in claim 1 or 2 wherein the carotenoid is selected from lycopene, alpha-carotene, beta-carotene, zeaxanthin, cryptoxanthin, lutein or mixtures thereof.

4. A composition as claimed in claims 1 to 3 wherein the ratio of (a) to (b) is from 1: 0.1 to 1: 10. .

5. A composition as claimed in any preceding claim, wherein component (b) is in the form of a vegetable extract which contains the component itself.

6. The composition of claim 5, wherein the vegetable extract is a tomato extract.

7. The composition of claim 6 wherein the tomato extract contains about 2-20% lycopene.

8. A composition as claimed in any preceding claim, wherein the pharmaceutically acceptable salt of L-carnitine or alkanoyl L-carnitine is selected from the group consisting of: a chloride; bromide; an iodide; aspartate, acidic aspartate; citrate, acid citrate; a tartrate salt; phosphates, acidic phosphates; fumarate, acid fumarate; glycerol phosphate; glucose phosphate; a lactate salt; a maleate salt; an acidic maleate salt; orotate salts; an acidic oxalate salt; sulfates, acidic sulfates; trichloroacetate salt; trifluoroacetate and methanesulfonate.

9. A composition as claimed in any preceding claim, further comprising vitamins, isozymes, minerals and antioxidants.

10. A composition as claimed in any preceding claim which is administered orally in the form of a dietary supplement.

11. A composition as claimed in any preceding claim, which is administered orally, parenterally, rectally, transdermally or by ocular instillation in the form of a medicament.

12. The dietary supplement of claim 10, which is useful for preventing diseases caused by the presence of free radicals due to environmental pollution and lipid peroxidation of atherosclerosis, blood vessels, heart or brain; proliferative alterations of tissue include prostate, uterine, breast or colon tissue; vision and retinal changes include cataracts and macular degeneration of the retina.

13. The medicament as claimed in claim 11, which is useful for treating diseases caused by the presence of free radicals due to environmental pollution and the lipid peroxidation phenomenon of atherosclerosis, blood vessels, heart or brain; proliferative alterations of tissue include prostate, uterine, breast or colon tissue; vision and retinal changes include cataracts and macular degeneration of the retina.

14. The dietary supplement of claim 12, in solid, semi-solid or liquid form.

15. The medicament of claim 13, which is in a solid, semi-solid or liquid form.

16. The dietary supplement of claim 14, in the form of tablets, lozenges, pills, capsules, granules or syrups.

17. The pharmaceutical as claimed in claim 13, which is in the form of tablets, troches, pills, capsules, granules, syrups, vials, eye washes and eye rinses or drops.