CA1136551A - Composition containing acetyl carnitine and other acyl derivatives of carnitine for treating hyperlipoproteinaemias and hyperlipidaemias - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE:
A therapeutic composition for the treatment of hyperlipidaemias and hyperlipoproteinaemias is disclosed. This composition comprises an effective amount of acetyl-carnitine and other acyl derivatives of carnitine or pharmaceutically acceptable salts, esters or amides thereof, sufficient to restore an abnormal lipid metabolism to normal, in mixture with a pharmaceutically acceptable carrier.

Description

113~i551 The present in~ention relates to a therapeutic composition for the treatment of hyperlipoproteinaemias, hyperlipideamias and some associated diseases thereof such as diabetes, atherosclerosis, nephrotic syndromes, etc., wherein impaired lipid metabolism can represent a high risk factor.
Carnitine and acyl derivatives thereof are normally present in the body.
Carnitine exerts the function of carrier o~ activated long-chain free fatty acids through the mitochondrial membrane which, being impermeable to acyl CoA derivatives, enables the long-chain free fatty acids to enter only when esterification with carnitire has taken place.
The carrier function of carnitine is exerted in two different directions:
- by transporting the active long-chain fatty acids from the sites of their biosynthesis, for example the microsomes, to the mitochondria where they are oxidized;
- by transporting acetyl CoA from the mitochondria, wherein it is formed, to the extramitochondrial sites where the synthesis of long-chain fatty acids occurs, e.g. in the microsomes wherein acetyl CoA can be utilized for synthesizing cholesterol and fatty acid.
Since the tissue levels and distribution of carnitine, acetyl carnitine and other acyl derivatives of carnitine are influenced by diet and by the nutritional state, therefore changes in the concentrations of carnitine and acyl derivatives thereof are associated with different pathological conditions, e.g. lipid accumulation, muscular dystrophies, etc.
A previous therapeutic use of carnitine has already been disclosed in the U S patents, 3,830,931 and 3,968,241 to De Felice in connection with the treatment of cardiac arrhythmias and impaired cardiac function associated ~ith congestive heart failure and shock. The use of acyl (e.g.
acetyl) derivatives of carnitine in therapy of myocardial anoxia, ischeamia, arrhythmic sindromes and heart failure has also been already disclosed in the literature.
Several drugs, among others nicotinic acid and its derivatives, clofibrate and dexthrothyroxine have long been ln gelleral use for ~he treatmcn~ oL hyperlipopro-telneami.ls and hyperlipideamias. It has bcen found, however, that, whilst they do not afford constantly reliable therapeutic 10 results, they are intolerably toxic, particularly in long-term treatment, and exhibit untoward side-effects.
For instance, clofibrate has side-effects including nausea, gastrointestinal discomfort possibly with diarrhoea, drowsiness, headache, and dizziness. Weight gain, myalgia, pruritus, skin rashes, alopecia, and leucopenia have also been reported.
In accordance with the present invention, there is proposed a therapeutic composition for the treatment of hyperlipoproteinaemias and hyperlipidaemias and 20 diseases related thereto which comprises an effective amount of an acyl derivative of carnitine represented hy the formula _ (CH3)3 _ N+ - CH CH - CH - COO
OR
wherein R represents a propionyl, hydroxybutyryl, stearoyl, acetoacetyl, succinyl, isovaleryl or crotonyl radical or an effective amount of pharmaceutically acceptable salts, esters and amides thereor, sufficient to restore an abnormal lipid metabolism to normal, in mixture with a pharmaceutically acceptable carrier.
It has been found that the composition of the present lnvention, whilst extremely effective in the treatment 113~5Sl of hyperlipoproteinaemias and hyperlipidaemias, overcomes the drawbacks of the prior art compositions, because-the above-identified acyl derivatives of carnitine are totally free of the side-effects of the previously known drugs.
The effects of the above acyl derivatives of carnitine and of some others not claimed herein, such as acetyl-carnitine, in the treatment of hyperlipoproteinaemias and hype~lipidaemias have been demonstrated in laboratory animal ! experimental models and clinical studies.
- In normal rats, after one administration of acetyl carnitine and the above listed acyl derivatives of carnitine at dose levels of 50-100 mg/kg and 400 mg/kg orally, intraperitoneally, intravenously and subcutaneously, the plasma levels of triglycerides and cholesterol were reduced (see Table 1).

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- In normal rats, two daily administrations prolonged for 7 consecutive days of acetyl carnitine and the other acyl derivatives of carnitine provoked a substantial reduction in the levels of total lipids, triglycerides _and cholesterol. (see Table 11).

- In 17-hr fasted rats, the increase of FFA due to lipid mobilization was strongly reduced by 100 mg/kg and 400 mg/kg doses of acetyl carnitine and the other acyl derivatives of carnitine given intraperitoneally in single administrations. (see Table 111).

An identical reduction was achieved in mice, rabbits and dogs (see Table IV) in the same experimental conditions.

- In rats, the 7ncrease in triglyceride plasma levels induced by a high--tr7glyceride diet (Tiengo A., International Conference on Atherosclerosis-Milan, Italy, Nov. 1977) was markedly reduced after oral administration of acetyl carnitine and the other acyl derivatives of carnitine twice daily for 7 successive days at a dose level of 200 mg/kg.

The 1'3 ~ lipoprotein fraction was also markedly reduced (see Table V).
- In rats, the hypertriglyceridaemia induced by the administration of olive oil (15 mg/kg via the oral route) was well antagonized by 500 mg/kg of acetyl carnitine or butyryl carnitine given intraperitoneally (see Table Vl).

-In rats and rabbits the increase in plasma cholesterol and-~3-lipoproteins induced by a high-cholesterol diet (Nath N., A. E. Harper and C. A. Elvelyem-J. of Nutr., 1959, 67~ 289) was strongly anatagonized by 100 and 300 mg kg of acetyl carnitine and acyl carn1tine derivatives given intraperitoneally or orally in two daily administrations for 7 consecutive days.

The high density lipoprotein (HDL) fraction which in hyperlipidaemic diet fed rats was reduced, increased in D, L-acetyl carnitine and L-acetyl carnitine treated animals, whereas the very low density lipoprotein (VLDL~

and low density lipoprotein (LDL) fractions were reduced as well as the VLDL + LDL/HDL ratio, showing that acyl (e. 9. acetyl) carnitine acts on the main mechanism responsible for atherosclerosis.

-In rats and dogs, administration of acetyl carnitine and other acyl derivatives of carnitine alters the lipoprotein levels, increasing the HDL fraction and reducing the LDL and VLDL fraction (see Table Vll).

-Serum glutamic oxalacetic transaminase (SGOT) and triglyceride serum levels 7n rats were increased by administering ethanol (4g/kg~ and restored to normal by 100-200 mg/kg doses of acetyl carnitine or other acyl derivatives of carnitine intraperitoneally, orally or =ubcutaneously. Hepatic hypertriglyceridaemia was reduced when hlgher doses - approximately 400-500 mg/kg - of D, L

acetyl carnitine and L- acetyl carnitine were given via the oral route (see TableVIII).

- In the dog the alkaline storage and ketone body levels disordered by fasting conditions and lipid infusion, are restored to normal values by 6-hr and 12-hr infusion of 5 mg of D, L acetyl orL-acetYI carnitine /kg/ hour. (see Table IX).

- Ir -_.s with diabetes induced by streptozotocin (60 mg/kg, 48 hours before carnitine treatment started), the blood glucose and plasma cholesterol and tr iglyceride levels were reduced by D, I-acetyl or L-acetyl carnitine ` . 1~36551 administered i.p. daily for five consecutive days at the dose of 1 g/kg (see Table X).
- In man, doses of 1-3 g of acetyl carnitine and ot~er acyl derivatives of carnitine given orally for 30 days consecutively reduced total lipids by 12-20%, ~-lipoproteins by 12-25%
and cholesterol by 18-20% (see Table XI) and provoked altered fatty acid (FF) levels with a decrease in palmitic, stearic and some unsaturated fatty acids: C 18, C 20, C 22 and C 24 which require the presence of carnitine for their transport across the mitochondrial membrane.
- In man, total plasma lipids and cholesterol in diabetic hyperlipideamia were reduced by -20, -35% and -25, ~45%
respectively after orally administering D,L-acetyl carnitine or L-acetyl carnitine in 500 mg, or 600 mg respectively, daily doses prolonged for 6 months (see Table XII).
- In patients suffering from hyperlipoproteinemias and hyperlipideamias, administration of D,L acetyl carnitine given in three daily doses of 500 mg each for 20 days - consecutively, has brought about a marked decrease of the total lipid~, associated with a remarkable lowering of the cholesterol levels and, above all, with a restoration of the lipoprotein LDL/HDL ratio to normal values, caused mainly by an increase of the HDL fraction (see Table XIII).
As known, carnitine contains an asimmetric carbon atom and consequently exists in two stereoisomers. Either the racemate or the isolated isomers can be conveniently used in the composition of the present invention, ... ..

~3~i551 although it appears that the L-isomer is more active, while the D-isomer is slightly more toxic. The tolerance of acetyl-carnitine and the other acyl derivatives of carnitine of formula (I), both in their racemate and optically active forms, is excellent, regardless of the route of administration being employed. As an instance, the LD50 in mice via the intra-venous route as assessed for the various acyl derivatives of carnitine of the present invention according to the Litchfield and Wilcoxon method is shown in the following Table A.
(Litchfield, J.T., and Wilcoxon, F., J. Pharm. Exptl. Therap.
96, 99. 1949).
Table A

LD50 mg/kg intravenously in mice acetyl-carnitine 770 propionyl-carnitine 761 butyryl-carnitine 742 hydroxy-butyryl-carnitine 745 hexanoyl-carnitine 695 octanoyl-carnitine 630 decanoyl-carnitine 736 palmitoyl-carnitine 750 stearoyl-carnitine 745 acetoacetyl-carnitine 728 succinyl-carnitine 780 isovaleryl-carnitine 734 crotonyl~carnitine 697 In actual practice, acyl carnitine (in either racemate or stereoisomer form) is given orally or parenter~

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113~55~
ally, in any of the usual pharmaceutical forms which are prepared with conventional procedures, well known to anyone having ordinary skill in this art. These forms include solid and liquid oral unit dosage forms such as tablets, capsules, solutions, syrups and the like, and injectable forms such as sterile solutions for ampoules and vial. Hereinbelow some non-limiting examples of compositions for oral and parenteral administration are given.
Example 1 Solution or sterile aqueous solution containing acetyl carnitine (in either racemate or stereoisomer form) or other acyl derivatives in concentrations from 50 mg to 500 mg per ml.
a) The excipient for injectable ampoules/vials is prepared in accordance with the following non-limitative composition:
sodium carboxymethyl cellulose........... 10 mg/ml ~at low viscosity) polysorbate 80............................ 4 mg/ml propylparaben........................... 0.4 mg/ml water for injections sufficient for 1 ml, 2 ml, 5 ml and 10 ml ampoules/vials.
b) The excipient for phleboclysis bottles containing 50 ml, 100 ml, 250~ml, 500 ml and 1000 ml is prepared in accordance with the following non-limitative composition:
NaCl..................................... 8.6 g/lt KCl...................................... 0.3 g/lt ... . _ _ .

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CaC12 ~ ---................................ 0.33 g/lt water for injection sufficient for 1 litre.

c) The excipient for bottles for oral use containing from 5 ml to 100 ml is prepared in accordance with the following non-limitative composition:
mannitol .................................. 11 mg/ml sorbitol .................................. 600 mg/ml sodium benzoate ........................... 3 mg/ml orange extract ............................ 200 mg/ml vitamin B12 ............................... 3 mg/ml sufficient purified water.

Example 2 Tablets containing from 25 mg to 500 mg of acetyl carnitine ~in either racemate or steroisomer form) or other acyl derivatives. The excipient is prepared in accordance with the following non-limitative composition:
starch .................................... 45 %

avicel (trademark) ........................ 45 %
talc ...................................... 10 %

Example 3 Capsules containing from 25 mg to 500 mg of acetyl carnitine (in either racemate or stereoisomer form) or other acyl derivatives, without excipients in a non-limita~

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sense. -, . _ . . . . .

113~i551 The dose which is administered will be determined by the attending physician having regard to the age, weight and condition of the patient, using sound professional judge-ment. Although effective results can be noticed at doses as low as from 5 to 8 mg/kg of body weight daily, a dose of from about 10 to about 50 mg/kg of body weight daily is preferred.
Should it be deemed necessary, larger doses can be safely administered, because of the extremely low toxicity of acetyl carnitine and the other acyl derivatives of carnitine of formula (I).
Hereinbelow, the procedures for carrying out the above-identified experiments, are set forth:
A) Study of the hypolipaemia-inducing effect in normal labora-tory animals. Evaluation of some serum biochemical para-meters in laboratory experimental animals after one single treatment or repeated treatments with varying doses of the substances under examination.
ASSUS E. et al. Therapie, 27, 395, 1972.
B) Study of the antilipolytic effect versus fasting-induced lipid mobilization. Evaluation of the serum free fatty acids and triglycerides at various time intervals after one single treatment with the substances under examination Carlsson L.A., Nye E.R. Acta Med. Scand. 179, 453, 1966 Dalton C., Van Trabert C., et al. Bioch. Pharmacol. 19.
2609, 1970 C) Study of the effect of the substances under examination versus the ethanol-induced hypertriglyceridaemia.
B.B. BRODIE, W.M. BUTLER et al.
Am. J. Clin. Nutr. 9, 432, 1961 D) The biochemical determinations of the examined parameters were carried out using the following procedures:
- Total lipids: Zoellner, N., K. Kirsch, Z. ges. exp. Med.

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113~i551 135, 545 (1962) : Biochemia test.
- Triglycerides: Van Handel,E., D.B. Zilversmit, J. Lab. Clin. Med. 50, 152, (1957) . ~

1136;551 1 2.
- Cholesterol: Zlatkis, A., Zack, A.K et al J. Lab. Clin. Med. 41, 485, (1953) - Free fatty acids: Dole, V. P., J. Clin. Investigation 35, 1 50, ( 1 956) Trout, D. L., et al. J. Lipid. Research, 1, 1 99, ( 1 960).

- SGOT (serum glutamic oxalacetic transaminasej:

Wrob lewski F.; J. S. La Due Proc. Soc. exp. Biol. Med. ~ 569, ~1956) - Lipoproteins: 8urstein, M.; J. Samai l le La presse Medicale 43, 974 (1958) Electrophoretic Method - Glucose: Enzymatic method - Biochemia test Werner, W., H. G. Rey et al.

Z. Analyt. Chem. 252, 224 (1970) 113~i55~

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Effect of D,L-acetylcarnitine, D-acetylcarnitine, L-acetylcarnitine and D,L-propionylcarnitine on the lipid mobilization in 17-hr fasted rat.
Mean value + SEM of F F A (free - fatty - acids) ~Eq/l two hrs after treatment.

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Effect of D,L-acetylcarnitine on the lipid mobilization in 17~hr fasted animals.
Mean + SEM of F F A ~free - fatty - acids) in Eq/l two hrs after treatment.

113~i551 animal no. treatment mg kg 1 route F F A ~ Eq~l mice 5 saline i.p. 2097.79 + 49.40 " D,L-acetylcarnitine 500 " 1631.31 + 46.04-rabbits 6 saline " 401.68 + 57.36 " D,L-acetylcarnitine 500 " 233.6C + 37.21 dogs 3 saline "1103.64 + 69.29 " D,L-acetylcarnitine 250 " 524.63 + 89.22 Student's t>~ test: , ~ and indicate respectively P < 5%, 1% and 1~ versus saline group.

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Claims (4)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A therapeutic composition for the treatment of hyperlipoproteinaemias and hyperlipidaemias and diseases related thereto, which comprises an effective amount of an acyl derivative of carnitine represented by the formula (I) wherein R represents a radical selected from the group consis-ting of propionyl, hydroxybutyryl, stearoyl, acetoacetyl, suc-cinyl, isovaleryl and crotonyl, or an effective amount of pharmaceutically acceptable salts, esters and amides thereof, sufficient to restore an abnormal lipid metabolism to normal, in mixture with a pharmaceutically acceptable carrier.

2. The composition of claim 1, wherein the amount of said acyl derivative of carnitine of formula (I) or the pharmaceutically acceptable salts, esters and amides thereof contained in each dose is ranging from 25 to 500 mg.

3. The composition of claim 1, wherein said carrier is a sterile aqueous solution and the amount of said acyl derivative of carnitine of formula (I) or the pharmaceutically acceptable salts, esters and amides thereof mixed with said carrier is ranging from 50 mg to 500 mg per ml of solution.

4. A pharmaceutical composition comprising an effective amount of an acyl derivative of carnitine represented by the formula (I) wherein R represents a radical selected from the group consisting of propionyl, hydroxybutyryl, stearoyl, acetoacetyl, succinyl, isovaleryl and crotonyl, or an effective amount of pharmaceutically acceptable salts, esters and amides thereof, in mixture with a pharmaceutically acceptable carrier.