Pharmaceutical composition comprising L- carnitine or alkanoyl L-carnitine for the prevention and treatment of diseases brought about by lipid metabolism disorders

Abstract

A pharmaceutical compositions comprising L-carnitine or alkanoyl L-carnitine and hydroxycitric or pantothenic acid or derivatives thereof for the prevention and treatment of diseases brought about by lipid metabolism disorders, is disclosed.

Description

[0001] The present invention relates to a novel therapeutic use of L-carnitine, some alkanoyl L-carnitines and the pharmacologically acceptable salts thereof in combination with hydroxycitric or pantothenic acid or derivatives thereof (wherein “derivatives thereof” also encompasses natural products and their extracts containing same for the prevention and therapeutic treatment of diseases brought about by lipid metabolism disorders, such as cardiovascular disorders, atherosclerosys, hyperlipidaemias and obesity, and for controlling and decreasing the appetite.

[0002] According to its broadest aspect the invention relates to the coordinated use of L-carnitine or an alkanoyl L-carnitine or the pharmacologically acceptable salts thereof with hydroxycitric or pantothenic acid or derivatives thereof. By “co-ordinated use” of the aforesaid compounds it is meant indifferently either the co-administration, i.e. the substantially concomitant supplementation of L-carnitine or alkanoyl L-carnitine or a pharmacologically acceptable salt thereof and hydroxycitric or pantothenic acid or a derivative thereof, as active ingredients, or the administration of a combination preparation comprising a mixture of the aforesaid active ingredients, in addition to suitable excipients, if any.

[0003] The present invention also relates to orally, parenterally, rectally or transdermally administrable pharmaceutical compositions suitable for treating the aforesaid disorders and for controlling and decreasing the appetite, which comprise, as active ingredients, L-carnitine or an alkanoyl L-carnitine or a pharmacologically acceptable salt thereof and hydroxycitric acid or pantothenic acid or derivative thereof. Preferred hydroxycitric acid derivatives are the salts and esters thereof and the natural products and their extracts containing same, as specified in more detail hereinbelow. It should be understood that whenever in the present specification reference is made for the sake of simplicity to “hydroxycitric acid”, the naturally occurring compound, i.e (−)-treo hydroxycitric acid, is meant.

[0004] Preferred pantothenic acid derivatives comprise 4′-phosphopantothenate, 4′-phosphopantothenylcisteine, 4′-phosphopantotheine, pantotheine and pantethine. Pantethine is particularly preferred.

[0005] Hydroxycitric acid and derivatives thereof may occur as extracts of natural products containing hydroxycitric acid at high concentrations, such as the extract of the fruits of Garcinia (Garcinia cambodia, Garcinia atroviridis, Garcinia indica, Garcinia citrin), of the fruits of Malabar Tamarind or Gorikapuli (Lewis Y. L., Neelakantan S., Phyto-chemistry 4, 619, 1965), (Streenivasan A., Vankataraman R., Current Science 4, 151, 1959) or other extract of natural products containing same.

[0006] A preferred salt of hydroxycitric acid is calcium hydroxycitrate.

[0007] The alkanoyl L-carnitines useful for the novel therapeutic use of the present invention are those wherein the alkanoyl group is a straight or branched group, having from 2 to 8 carbon atoms, preferably from 2 to 6 carbon atoms Particularly preferred are acetyl, propionyl, butyryl, valeryl and isovaleryl L-carnitine.

[0008] Pharmaceutically acceptable salts of L-carnitine or alkanoyl L-carnitine include, in addition to the inner salts, any salt of these with acids which do not give rise to undesired or side effects. The formation of pharmaceutically acceptable acid addition salt is well known to the experts in pharmacy and pharmaceutical technology.

[0009] Non-limiting examples of suitable salts include the chloride, bromide, orotate, acid aspartate, acid citrate, acid phosphate, fumarate, acid fumarate, lactate, maleate, acid maleate, acid oxalate, acid sulfate, glucose phosphate, tartrate and acid tartrate salts.

[0010] Previous therapeutic uses of L-carnitine are already known.

[0011] For instance L-carnitine has been used in the cardiovascular field in the treatment of acute and chronic myocardial ischaemia, angina pectoris, cardiac arrhythmias and insufficiency, and peripheral vascular diseases.

[0012] In nephrology, L-carnitine has been administered to chronic uraemic patients who are subjected to regular haemodialysis treatment with a view to counteracting muscular asthenia and the onset of muscular cramps.

[0013] Moreover, U.S. Pat. No. 3,810,994 (Ethyl Corporation) discloses the therapeutic utility of pharmaceutical compositions of L-carnitine or salts or esters thereof, for the treatment of obesity.

[0014] U.S. Pat. No. 4,255,449 (Cavazza) and U.S. Pat. No. 4,268,524 (Cavazza) disclose the use of L-carnitine and alkanoyl L-carnitine to normalize the abnormal ratio between low density lipoprotein (LDL)+ very low density lipoproteins (VLDL) and high density lipoprotein (HDL) which is an aetiological factor for various cardiovascular diseases.

[0015] As known, through the beta-oxidation of fatty acids L-carnitine is capable of preventing their accumulation and of supplying the energy requirement of cells (Bremer Y., TIBS 2, 207, 1977) via modulation of extra- and intramitochondrial CoA.

[0016] The carnitine pool not only regulates the bio-oxidation of intramitochondrial fatty acids, but also inhibits the formation of triglycerides (Bieber L. L., J. Biol. Chem. 254, 8163, 1979; Pande D. V., Proc. Nat. Acad. Sci. USA 72, 883, 1975).

[0017] Hydroxycitric acid, too, has for some time now been known as a metabolic factor. It is present, in fact, in large amounts in a number of plants used as foodstuffs and, in particular, in Malabar Tamarind and in the fruits of various species of Garcinia and its extraction and isolation have permitted extensive biochemical and pharmacological study of the substance. Recent data have revealed its importance as a regulator of the synthesis of cholesterol and fatty acids (Hamilton Y. G., Lipids 12, 1, 1976).

[0018] Hydroxycitric acid is capable of inhibiting the activity of ATP-citratolyase, an enzyme which catalyses the extramitochondrial conversion of citrates to oxoacetates and acetyl Coenzyme A.

[0019] The importance of this enzyme consists in its ability to maintain the Coenzyme A pool necessary for lipid and cholesterol synthesis. The enzymatic reaction catalysed by citratolyase which leads to the synthesis of cholesterol and fatty acids from carbohydrates is inhibited by hydroxycitric acid which together with the reduction in lipid synthesis also leads to a greater storage of carbohydrates in the form of glycogen in the liver (Berkbout T. A., Biochem. J. 48, 6, 1990: Triscari Y., Sullivan A. C., Lipids 12, 357, 1976; Watson Y. A., Fang M., Arch. Biochem. Biophys. 135, 209, 1969).

[0020] Both L-carnitine and hydroxycitric acid are, therefore, capable of exerting an action upon lipid metabolism via different mechanisms: on the one hand, L-carnitine facilitates the oxidation and intramitochondrial utilization of fatty acids and prevents the accumulation of triglycerides, and, on the other, hydroxycitric acid prevents their actual synthesis (Lowenstein Y. M., J. Biol. Chem. 246, 629, 1971; Hood R. L., Comp. Biochemical Physiol. 81B, 667, 1985).

[0021] What have proved very surprising and unexpected, however, are the synergistic effects which can be obtained on energy metabolism and on lipid metabolism by combining these two compounds or by coordinately administering them.

[0022] This unexpected synergistic effect obtained by the co-ordinated use of L-carnitine or its derivatives and hydroxycitric or pantothenic acid or derivatives thereof has been demonstrated in numerous studies, so much so, indeed, as to suggest that this combination can be used to advantage in facilitating the elimination of lipids and cholesterol from tissues, in the treatment of cardiovascular diseases, and in preventing abnormal formation and accumulation of fats.

[0023] The research conducted to date has shown that the coordinated use of the two compounds proves surprisingly effective in inhibiting the formation of atherosclerosis and the infiltration of tissues, as well as the formation of cholesterol and triglycerides.

[0024] In addition to the anticholesterolaemic and antidyslipidaemic effects induced by this combination, the research has also revealed a reduction of appetite and reduced food consumption with consequent weight loss.

[0025] This new pharmaceutical composition can, therefore, be used in the prevention and treatment of all those disease conditions related to a high concentration of cholesterol and lipids in the tissues, such as, for instance, atherosclerosis, hypercholesterolaemia, and cardiovascular diseases, and in the treatment of obesity.

[0026] The toxicological results are reported below, as are the results of the most significant studies in terms of evidence of the surprising synergistic effect that can be obtained with a combination of L-carnitine or one of its derivatives and hydroxycitric acid or one of its derivatives. The data reported in these studies demonstrate the unexpected potentiation of action obtainable with this new composition and that important practical applications stem from this activity in the pharmaceutical, dietary and alimentary fields for the prevention or therapy of numerous disease conditions related to lipid metabolism disorders, such as atherosclerosis, hypercholesterolaemia” obesity and cardiovascular diseases.

[0027] Toxicology

[0028] The tests performed, administering a combination of L-carnitine or its derivatives and calcium hydroxycitrate or an extract from Garcinia cambogia (with a roughly 30% hydroxycitrate concentration) in a single dose at high concentrations, have demonstrated the good tolerability of the new composition. High doses of L-carnitine or its derivatives (1 g/kg) could be administered, in fact, together with high doses of calcium hydroxycitrate (up to and above 1 g/kg) or of Garcinia cambogia hydroxycitrate extract (2 g/kg), orally to Wistar rats, without any evidence of signs of toxicity related to the administration of any of the various presentation forms which the composition according to the invention can take on. The good tolerability of the composition has also been established through prolonged oral administration of the product together with the diet for three consecutive months in both male Wistar rats and in mice.

[0029] Tests in experimentally obese rats

[0030] Male Wistar rats aged about 2 months were fed on a lipogenic diet (50% glucose, 20% casein, 4% cellulose, 5% salt mixture, 1% hazel nut oil, 18% starch, 1% vitamin mixture).

[0031] This diet was administered for fifteen days consecutively to different groups of rats, one of which served as a control group, whereas in the other groups the diet was administered together with calcium hydroxycitrate (1%-2%) or Garcinia cambogia extract (2%-4%) or L-carnitine (2%-4%) or acetyl L-carnitine or propionyl L-carnitine at the same doses, or together with various combinations of these products at the same doses. At the end of the fifteenth day of treatment, food consumption was evaluated in treated rats vs. controls and increases in body weight and in serum triglycerides and epididymal fat were measured.

[0032] Food consumption results

[0033] During the fifteen days of treatment on a lipogenic diet a substantial reduction in daily food consumption was detected in the animals treated with calcium hydroxycitrate or with Garcinia cambogia extract. No changes compared to controls were noted, on the other hand, in rats treated with L-carnitine, propionyl L-carnitine or acetyl L-carnitine. The reduction in food consumption was, however, much more marked in the group of animals treated with the combination of calcium hydroxycitrate plus L-carnitine, acetyl L-carnitine, and particularly propionyl L-carnitine, even as compared to that detected in the rats treated with calcium hydroxycitrate or Garcinia cambogia extract.

[0034] Whereas, with the largest dose of calcium hydroxycitrate, the daily food consumption dropped from an initial values of 18.8 g to a value of 15.1 g after fifteen days' treatment, the respective values for the lower dose were 19.2 g and 17.1 g.

[0035] The non-significant changes detected with the two doses of L-carnitine, acetyl L-carnitine and propionyl L-carnitine become highly significant when these products are combined even with the lower doses of calcium hydroxycitrate or Garcinia cambogia extract.

[0036] In the animals treated with the combination of calcium hydroxycitrate and propionyl L-carnitine at the lower doses, this leads, for example, to a reduction in food consumption from 18.4 g to 13.2 g, thus demonstrating a potentiation of the effect on the reduction of food intake. A similar, though more limited, degree of potentiation is observed in the data for the combination of the various carnitines with Garcinia cambogia extract (Table 1).

[0037] Body weight results

[0038] Body weight gain is also reduced by the administration of calcium hydroxycitrate in correlation with the dose administered. In these tests, too, while no significant changes are detectable with the administration of carnitines alone, highly significant changes are observed when the carnitines are combined with calcium hydroxcitrate or with Garcinia cambogia extract. In the group of animals treated with the combination of calcium hydroxycitrate plus carnitines, the reduction in body weight gain is much greater than that obtainable with administration of the highest dose of calcium hydroxycitrate alone (Table 2).

[0039] Serum triglyceride and epididymal fat results

[0040] The potent synergistic effect between carnitines and calcium hydroxycitrate or Garcinia cambogia extract is clearly demonstrated by the results regarding serum triglyceride and epididymal fat values in rats on a lipogenic diet. After fifteen days of treatment a powerful effect in terms of a reduction in both parameters was detectable, in fact, in the group of animals treated with the combination of carnitines plus calcium hydroxycitrate or Garcinia cambogia extract.

[0041] Among the carnitines, the most effective was propionyl L-carnitine, which, when combined with calcium hydroxycitrate, maintains both serum triglycerides and epididymal fats practically within normal levels (Table 3).

[0042] Experimental hypertrigyceridaemia tests

[0043] In these tests, male Wistar rats serum triglyceride elevation was induced experimentally by means of the oral administration of fructose according to the method disclosed by L. A. V. Carlson (J. Atheroscler. Res. 8, 667, 1968; Atherosclerosis 16, 349, 1972). In the 5-day period prior to administration of 3 g of fructose, the rats, divided into groups, were treated with L-carnitine or its derivatives or with calcium hydroxycitrate or Garcinia cambogia extract at different doses, or with various combinations of these products.

[0044] The administration of these products was then repeated two hours after administration of fructose, and 5 hours later all animals were sacrificed. Triglyceride assay was then performed according to the method of R. K. Donabedian (Clin. Chem 20, 632, 1974). The results obtained in these tests demonstrate that the fructose-induced hypertriglyceridaemia is not modified by the administration of carnitines, whereas it is reduced by the administration of calcium hydroxycitrate or Garcinia cambogia extract. The hypertriglyceridaemia-reducing effect is, however, substantially increased and potentiated when the calcium hydroxycitrate or Garcinia cambogia extract is combined with the carnitines. The potentiating effect is marked for all carnitines, but most notably in the case of propionyl L-carnitine.

[0045] Experimental atherosclerosis tests

[0046] Also in atherosclerotic vascular lesions induced experimenatlly according to the method of M. R. Malinow (Atherosclerosis 48, 105, 1983), with administration of an atherogenic diet (24% casein, 10% cotton oil, 5% salt, 60% sugar, 1% cholesterol, Vit D2 200 mUST/g of diet) for six weeks consecutively to different groups of male Wistar rats, it has been shown that the combination of carnitines plus calcium hydroxycitrate or Garcinia cambogia extract is capable of substantially potentiating the anti-atherogenic effect.

[0047] This was assessed by measuring the thickness of the abdominal aorta and the intensity of staining induced by Sudan IV using a scoring system from 1 to 5, according to degree of severity. By means of this assessment, it was clearly demonstrated that both L-carnitine and calcium hydroxycitrate or Garcinia cambogia extract are capable of reducing the severity of the atherosclerotic lesions. The incidence of these lesions, however, is substantially inhibited to the point of complete elimination in the groups of animals treated with a combination of these products.

[0048] The incidence of atherosclerotic lesions was completely inhibited particularly with the combination of calcium hydroxycitrate and propionyl L-carnitine. These tests, too, therefore, demonstrate the intense synergistic action of carnitines and calcium hydroxycitrate.

[0049] Experimental hypercholesterolaemia tests

[0050] The results of tests conducted in Wistar rats with hypercholesterolaemia induced by diet according to the method described by C. R. Sirtori (Atherosclerosis 26, 78, 1977) also confirm the surprisingly marked potentiating effect of calcium hydroxycitrate plus carnitines in reducing cholesterol values. Treatment both with L-carnitine and with calcium hydroxycitrate or with Garcinia cambogia extract, or with a combination of these products, was initiated together with a hypercholesterolaemia-inducing diet and continued for six weeks consecutively. At the end of this period, the assay was performed on the serum of the control animals and on that of the treated animals according to the method described by P. Roschlan (Clin. Chem. Clin. Biochem. 12, 403, 1975). The total cholesterol values observed showed a fair degree of lowering induced both by the treatment with calcium hydroxycitrate and by the treatment with Garcinia cambogia extract. Practically normal cholesterolaemia values were restored in the animals treated with the combination of calcium hydroxycitrate plus carnitines, thus demonstrating a marked synergistic effect between these two compounds characterizing the novel composition according to the present invention.

[0051] The following non-limiting examples illustrate some compositions according to the present invention.

EXAMPLES

[0052] 1 1) L-carnitine mg 500 Calcium hydroxycitrate mg 300 2) Acetyl L-carnitine mg 500 Calcium hydroxycitrate mg 300 3) Propionyl L-carnitine mg 500 Calcium hydroxycitrate mg 300 4) Isovaleryl L-carnitine mg 500 Calcium hydroxycitrate mg 300 5) Valeryl L-carnitine mg 500 Calcium hydroxycitrate mg 300 6) Butyryl L-carnitine mg 500 Calcium hydroxycitrate mg 300 7) L-carnitine mg 500 Garcinia cambodia extract mg 500 (30% hydroxycitric acid) 8) Acetyl L-carnitine mg 500 Garcinia cambodia extract mg 500 (30% hydroxycitric acid) 9) Propionyl L-carnitine mg 500 Garcinia cambodia extract mg 500 (30% hydroxycitric acid) 10) Isovaleryl L-carnitine mg 500 Garcinia cambodia extract mg 500 (30% hydroxycitric acid) 11) Valeryl L-carnitine mg 500 Garcinia cambodia extract mg 500 (30% hydroxycitric acid) 12) Butyryl L-carnitine mg 500 Garcinia cambodia extract mg 500 (30% hydroxycitric acid) 13) L-carnitine 500 mg, calcium hydroxycitrate 300 mg, Beta carotene 12500 I.V., Vit. B2 15 mg, Vit. C 100 mg. Vit. D3 200 I.V., Vit. B12 1.5 mcg, Folic acid 200 mcg, Vit. E 10 mg, Iron (as FeSO4) 32 mg, Manganese (as MnSO4) 5 mg, Zinc (as Zn acetate) 5 mg, Phosphorus (as Na2HPO4) 25 mg, Molybdenum 7,5 mg, Potassium 7,5 mg, Chromium 15 mcg, Selenium 40 mcg. 14) L-carnitine g 1.223 pantethine g 0.500 methyl-p-hydroxybenzoate g 0.015 sorbitol g 1.000 sodium saccharinate g 0.060 citric acid g 0.120 sodium hydroxyde g 0.032 bigarade flavour g 0.050 orange flavour g 0.010 pure water, balance to ml 10.0

[0053] 2 TABLE I MEAN DAILY FOOD CONSUMPTION (g) PER ANIMAL Before treatment After 15 days Calcium hydroxycitrate 19.2 ± 0.65 17.1 ± 0.35 (g 1/100 g diet) Calcium hydroxycitrate 18.8 ± 0.44 15.1 ± 0.46 (g 2/100 g diet) L-carnitine 17.3 ± 0.35 181.1 ± 0.50  (g 2/100 g diet) L-carnitine 18.4 ± 0.61 17.8 ± 0.41 g 4/100 g diet) Acetyl L-carnitine 18.6 ± 0.39 18.4 ± 0.44 (g 2/100 g diet) Acetyl L-carnitine 18.2 ± 0.41 18.8 ± 0.57 (g 4/100 g diet) Propionyl L-carnitine 17.7 ± 0.56 17.1 ± 0.38 (g 2/100 g diet) Poprionyl L-carnitine 18.2 ± 0.44 18.5 ± 0.48 (g 4/100 g diet) Garcinia cambodia 17.9 ± 0.34 16.8 ± 0.44 (g 4/ 100 g diet) Calcium hydroxycitrate 18.9 ± 0.61 14.4 ± 0.50 (g 1/100 g diet) + L-carnitine (g 2/100 g diet) Calcium hydroxycitrate 19.1 ± 0.58 14.8 ± 0.64 (g 1/100 g diet) + Acetyl L-carnitine (g 2/100 g diet) Calcium hydroxycitrate 18.4 ± 0.49 13.2 ± 0.53 (g 1/100 g diet) + Propionyl L-carnitine (g 2/100 g diet) L-carnitine 18.1 ± 4.7  15.9 ± 4.1  (g 2/100 g diet) + Garcinia cambodia (g 4/100 g diet) Acetyl L-carnitine 18.8 ± 3.9  16.2 ± 4.9  (g 2/100 g diet) + Garcinia cambodia (g 4/100 g diet) Propionyl L-carnitine 18.1 ± 4.8  14.4 ± 4.7  (g 2/100 g diet) + Garcinia cambodia (g 4/100 g diet)

[0054] 3 TABLE 2 BODY WEIGHT INCREASE AFTER 15 DAY-TREATMENT Final body weight increase (g) Controls 62.8 ± 3.5 Calcium hydroxycitrate 46.6 ± 4.1 (g 1/100 g diet) Calcium hydroxycitrate 38.9 ± 3.8 (g 2/100 g diet) L-carnitine 66.2 ± 4.9 (g 2/100 g diet) L-carnitine 64.5 ± 5.1 (g 4/100 g diet) Acetyl L-carnitine 60.4 ± 7.1 (g 2/100 g diet) Acetyl L-carnitine 60.1 ± 6.1 (g 4/100 g diet) Propionyl L-carnitine 62.4 ± 3.9 (g 2/100 g diet) Poprionyl L-carnitine 58.7 ± 3.7 (g 4/100 g diet) Garcinia cambodia 51.4 ± 3.3 (g 4/100 g diet) Calcium hydroxycitrate 28.7 ± 4.4 (g 1/100 g diet) + L-carnitine (g 2/100 g diet) Calcium hydroxycitrate 31.6 ± 3.9 (g 1/100 g diet) + Acetyl L-carnitine (g 2/100 g diet) Calcium hydroxycitrate 24.4 ± 2.8 (g 1/100 g diet) + Propionyl L-carnitine (g 2/100 g diet) L-carnitine 38.6 ± 3.1 (g 2/100 g diet) + Garcinia cambodia (g 4/100 g diet) Acetyl L-carnitine 36.8 ± 4.4 (g 2/100 g diet) + Garcinia cambodia (g 4/100 g diet Propionyl L-carnitine 34.8 ± 6.5 (g 2/100 g diet) + Garcinia cambodia (g 4/100 g diet)

[0055] 4 TABLE 3 SERUM TRIGLYCERIDES AND EPIDIDIMAL FAT AFTER 15 DAY-TREATMENT Triglycerides Epididimal fat (mg/100 ml) (g) Controls 94.68 ± 6.6 4.65 ± 0.41 Calcium hydroxycitrate 76.84 ± 6.9 3.91 ± 0.36 (g 1/100 g diet) Calcium hydroxycitrate 73.66 ± 7.1 3.32 ± 0.39 (g 2/100 g diet) L-carnitine 92.55 ± 7.7 4.21 ± 4.1 (g 2/100 g diet) L-carnitine 90.44 ± 6.8 4.34 ± 2.9 (g 4/100 g diet) Acetyl L-carnitine 95.81 ± 8.2 4.10 ± 3.8 (g 2/100 g diet) Acetyl L-carnitine  90.8 ± 7.5 4.15 ± 3.5 (g 4/100 g diet) Propionyl L-carnitine  88.4 ± 8.16 4.19 ± 4.4 (g 2/100 g diet) Poprionyl L-carnitine  82.7 ± 6.6 4.0 ± 5.6 (g 4/100 g diet) Garcinia cambodia  80.4 ± 7.3 3.85 ± 3.5 (g 4/100 g diet) Calcium hydroxycitrate  71.5 ± 6.7 3.25 ± 2.9 (g 1/100 g diet) + L-carnitine (g 2/100 g diet) Calcium hydroxycitrate  68.2 ± 5.5  3.0 ± 2.7 (g 1/100 g diet) + Acetyl L-carnitine (g 2/100 g diet) Calcium hydroxycitrate  60.5 ± 7.4 2.25 ± 2.2 (g 1/100 g diet) + Propionyl L-carnitine (g 2/100 g diet) L-carnitine  75.4 ± 3.1 3.50 ± 3.1 (g 2/100 g diet) + Garcinia cambodia (g 4/100 g diet) Acetyl L-carnitine  72.3 ± 4.4 3.25 ± 4.3 (g 2/100 g diet) + Garcinia cambodia (g 4/100 g diet Propionyl L-carnitine  70.3 ± 5.6 2.95 ± 3.8 (g 2/100 g diet) + Garcinia cambodia (g 4/100 g diet)

[0056] 5 TABLE 4 TEST ON EXPERIMENTALLY-INDUCED HYPERTRIGYCERIDAEMIA (mg/100 ml) Controls 195.8 ± 9.8 Calcium hydroxycitrate 170.6 ± 8.5 (g 0.5/Kg) Calcium hydroxycitrate 145.5 ± 8.5 (g 1/Kg) L-carnitine 190.4 ± 9.6 (g 0.5/Kg) L-carnitine 190.8 ± 8.6 (g 1/Kg) Acetyl L-carnitine 191.2 ± 9.1 (g 0.5/Kg) Acetyl L-carnitine 188.4 ± 5.5 (g 1/Kg) Propionyl L-carnitine 184.2 ± 6.8 (g 0.5/Kg) Poprionyl L-carnitine 180.4 ± 7.9 (g 1/Kg) Garcinia cambodia 170.6 ± 5.4 (g 0.5/Kg) Calcium hydroxycitrate 125.8 ± 9.1 (g 0.5/Kg) + L-carnitine (g 0.5/Kg) Calcium hydroxycitrate 120.4 ± 8.8 (g 0.5/Kg) + Acetyl L-carnitine (g 0.5/Kg) Calcium hydroxycitrate   108 ± 9.4 (g 0.5/Kg) + Propionyl L-carnitine (g 0.5/Kg) Garcinia cambodia 145.4 ± 8.6 (g 0.5/Kg) + L-carnitine (g 0.5/Kg) Garcinia cambodia 140.4 ± 7.4 (g 0.5/Kg) + Acetyl L-carnitine (g 0.5/Kg) Garcinia cambodia   125 ± 8.5 (g 0.5/Kg) + Propionyl L-carnitine (g 0.5/Kg)

[0057] 6 TABLE 5 TESTS ON EXPERIMENTALLY-INDUCED HYPERCHOLESTEROLEMIA (TOTAL CHOLESTEROL mg/dl) Controls  92.5 ± 4.4 Hypercholesterolemic controls 270.5 ± 10.4 Calcium hydroxycitrate 196.6 ± 9.6 (g 1/100 g diet) Calcium hydroxycitrate 180.5 ± 8.1 (g 2/100 g diet) L-carnitine 270.4 ± 5.1 (g 2/100 g diet) L-carnitine 260.6 ± 4.4 (g 4/100 g diet) Acetyl L-carnitine 266.7 ± 7.7 (g 2/100 g diet) Acetyl L-carnitine 255.4 ± 9.4 (g 4/100 g diet) Propionyl L-carnitine 250.6 ± 10.1 (g 2/100 g diet) Poprionyl L-carnitine 235.3 ± 9.6 (g 4/100 g diet) Garcinia cambodia 250.7 ± 4.7 (g 4/100 g diet) Calcium hydroxycitrate 155.8 ± 8.8 (g 1/100 g diet) + L-carnitine (g 2/100 g diet) Calcium hydroxycitrate 150.5 ± 7.1 (g 1/100 g diet) + Acetyl L-carnitine (g 2/100 g diet) Calcium hydroxycitrate 110.6 ± 6.6 (g 1 100 g diet) + Propionyl L-carnitine (g 2/100 g diet) L-carnitine 179.6 ± 9.6 (g 2/100 g diet) + Garcinia cambodia (g 4/100 g diet) Acetyl L-carnitine 165.9 ± 8.9 (g 2/100 g diet) + Garcinia cambodia (g 4/100 g diet Propionyl L-carnitine 155.5 ± 6.8 (g 2/100 g diet) + Garcinia cambodia (g 4/100 g diet)

Claims

1. An orally, parenterally, rectally or transdermally administrable pharmaceutical composition for treating cardiovascular, thromboembolic, atherosclerotic, hyperlipidemic disorders and obesity and for decreasing appetite, comprising L-carnitine or an alkanoyl L-carnitine wherein the alkanoyl group is a straight or branched alkanoyl having 2-8, preferably 2-6, carbon atoms or a pharmacologically acceptable salt thereof, and hydroxycitric acid or pantothenic acid or derivative thereof as active ingredients, and a pharmacologically acceptable excipient.

2. The composition of

claim 1, wherein the alkanoyl group is selected from acetyl, propionyl, butyryl, valeryl and isovaleryl.

3. The composition of claims 1 or 2, wherein the hydroxycitric acid derivative is a salt or ester thereof, a natural product or extract thereof containing same.

4. The composition of claims 1 or 2, wherein the pantothenic acid derivative is selected from the group comprising 4′-phosphopantothenate, 4′-phosphopantothenylcisteine, 4′-phosphopantotheine, pantotheine and pantethine.

5. The composition of

claim 3, wherein the hydroxycitric acid derivative is calcium hydroxycitrate.

6. The composition of

claim 3, wherein said extract is the extract from the fruits of Garcinia (Garcinia cambodia, Garcinia atroviridis, Garcinia indica, Garcinia citrin), or Malabar Tamarind or gorikapuli.

7. The composition of anyone of the preceding claims, wherein the weight ratio between hydroxycitric acid or derivative thereof and L-carnitine, alkanoyl L-carnitine or pharmacologically acceptable salt thereof is from 1:1 to 1:100, and wherein the weight ratio between pantothenic acid or derivative thereof and L-carnitine, alkanoyl L-carnitine or pharmacologically acceptable salt thereof is from 10:1 to 1:100.

8. The composition of anyone of the preceding claims which further comprises vitamins, mineral salts, antioxidants and vegetal fibers.

9. The composition of anyone of the preceding claims in a solid, semisolid, liquid, semiliquid, powder, granular or liposomic form, as tablets, capsules, granulates, powders and vials suitable for oral, parenteral, rectal or topic administration.

10. Co-ordinated use of L-carnitine or alkanoyl L-carnitine wherein the alkanoyl group has 2-8, preferably 2-6, carbon atoms, or pharmacologically acceptable salt thereof, and hydroxycitric acid or pantothenic acid or derivative thereof for treating cardiovascular, thromboembolic, atherosclerotic, hyperlipidaemic disorders and obesity, and for controlling and decreasing the appetite.