CA2377128C - Composition for the prevention of muscle fatigue and skeletal muscle adaptation to strenuous exercise - Google Patents

Composition for the prevention of muscle fatigue and skeletal muscle adaptation to strenuous exercise Download PDF

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Publication number
CA2377128C
CA2377128C CA002377128A CA2377128A CA2377128C CA 2377128 C CA2377128 C CA 2377128C CA 002377128 A CA002377128 A CA 002377128A CA 2377128 A CA2377128 A CA 2377128A CA 2377128 C CA2377128 C CA 2377128C
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carnitine
composition
state
fatigue
phosphate
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CA002377128A
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CA2377128A1 (en
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Claudio Cavazza
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Alfasigma SpA
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Sigma Tau Industrie Farmaceutiche Riunite SpA
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/15—Vitamins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Abstract

A composition is disclosed suitable for the prevention and/or treatment of muscular energetic deficiencies and states of asthenia for enhancing sport performances and for the treatment of states of heart fatigue, that may take the form of a dietary sup-plement, dietetic support or of an actual medicine, which comprises as characterizing active ingredients a combination of L-carnitine and/or at least one alkanoyl L-carnitine and creatinol-phosphate.

Description

Composition for the prevention of muscle fatigue and skeletal muscle adaptation to strenuous exercise The present invention relates to a composition for the prevention and treatment of muscular energetic deficiencies, states of asthenia and muscle fatigue, states of heart fatigue and post-infarct conditions and for enhancing sporting performances.

Accordingly, the composition may take the form and exert the action of a dietary supplem ent or of an actual medicine, depending upon the support or preventive action, or the strictly therapeutic action, which the composition is intended to exert in relation to the particular individuals it is to be used in.

More particularly the present invention relates to an orally, parenterally, rectally or transdermally administrable combination composition which comprises as characterizing ingredients:
(a) at least one carnitine selected from the group consisting of L-carnitine, acetyl L-carnitine, propionyl L-carnitine, butyryl L-carnitine, valeryl L-carnitine and isovaleryl L-carnitine or a pharmacologically acceptable salt thereof, and (b) creatinol-phosphate or a pharmacologically acceptable salt thereof.

la Suitably the weight ratio (a):(b) is from 1:0.1 to 1:1.
Compositions comprising carnitines and creatine or phosphocreatine are already known. WO 98/43499 (Sigma-Tau) discloses a nutritional supplement for facilitating the adaptation of skeletal muscle in indi.viduals undergoing programs of strenuous exercise and counteracting defatigation and weariness in asthenic individuals, which comprises a combination of L-carnitine, acetyl L-carnitine and propionyl L-carnitine as basic active ingredients which may also comprise creatine and/or phosphocreatine as optionally additive components.

US patent 4,376,117 (Simes) discloses the magnesium salt of creatinol-O-phosphate which is useful in the treatment and prevention of myocardiac infarction.

Both carnitine and creatinol-phosphate [1-(2-hydroxyethyl)-1-methylguanidine-O-phosphate] are well known for their important metabolic and pharmacological effects which have led to several positive pharmacological and clinical findings.

The carnitines are known to play a major role in the processes of beta-oxidation of fatty acids in the formation of ATP. They are also endowed with important antioxidant activity as demonstrated by their protective effect on lipid peroxidation of the cellular phospholipid membranes and on oxidative stress induced at the myocardial and endothelial cells level. These biochemical effects of the carnitines are
2 reflected by the favourable results obtained in clinical practice with their use in the treatment of various forms of atherosclerosis, myocardial ischaemia, peripheral vasculopaties and diabete.

Creatinol-phosphate, which is a compound structurally akin to creatine phosphate, from which it differs in its greater stability and in various metabolic and pharmacodynamic aspects, belongs to that group of phosphagens which play a fundamental role in muscle energy processes. It is known, in fact, that creatine phosphate is strongly involved in the processes responsible, in muscles, for ATP synthesis which is reduced during muscular exercise.

Creatine, creatine phosphate, creatine phosphokinase, ATP and ADP
are fundamental biochemical structures responsible for muscle function, particularly in anaerobic conditions. However, creatine, above all others, is the essential compound conditioning the remaining steps, its presence being of fundamental importance for achieving phosphorylation and the associated ATP-related energy processes. Its administration leads, in fact, to an increase in its muscular concentration and to an increase in creatine phosphate.

To obtain these effects in human subjects, however, the administration of high doses of creatine is necessary, up to and beyond 20 g per day, with consequent adverse side effects, particularly at the renal level.
Even though only approximately a quarter of the creatine administered can be transformed into creatine phosphate, administration of the latter is not a practical proposition on account of its instability and the difficulty of oral administration. It would, therefore, appear to be of great interest to provide another phosphorous-bearing derivative belonging to the pool of organic phosphates which is endowed with great stability and excellent tolerability and can also be administered orally, such as creatinol-phosphate, the administration of which, even at low doses, induces a substantial increase in muscular creatine and the consequent formation of creatine phosphate. Its administration causes an increase in muscular strength in human subjects, which is
3 also marked in the elderly, as well as the disappearance of asthenia and muscular weakness in convalescent subjects and the restoration of cardiac efficiency in subjects who have suffered an infarct.

Potentially even more interesting, however, also with a view to its action on muscular activity, are the results of experiments indicating its ability to stabilise the cell membranes which may be more resistant to attack by reactive oxygen species (ROS).

Since, as is known, one of the effects that forced muscular exercise may induce at muscle level are lesions of the muscle fibres themselves related to oxygen toxicity and to the products of lipid peroxidation, one of the favourable effects of creatinol-phosphate consists in its ability to protect the musculature against ROS-induced lesions.

It has now surprisingly been found,that a combination composition comprising as its characterising components:
(a) at least one carnitine selected from the group consisting of L-carnitine, acetyl L-carnitine, propionyl L-carnitine, butyryl L-carnitine, valeryl L-carnitine and isovaleryl L-carnitine or a pharmacologically acceptable salt thereof, and (b) creatinol-phosphate or its pharmacologically acceptable salt, is extremely effective for the prevention and treatment of muscular energy deficiencies, states of asthenia and muscle fatigue, states of heart fatigue and postinfarct conditions, and for enhancing sporting performance, owing to the potent, unexpected synergistic effect exerted by its components.

3a In a use aspect, the invention provides use of the composition of the invention, for preparing a medicament for the therapeutic treatment of a muscular energetic deficiency, a state of asthenia and muscle fatigue or a state of heart fatigue and post-infarct condition.

In a further aspect, the invention provides use of the composition of the invention, for the therapeutic treatment of a muscular energetic deficiency, a state of asthenia and muscle fatigue or a state of heart fatigue and post-infarct condition.

The invention also provides a commercial package comprising the composition of the invention, and associated therewith instructions for the use thereof in the therapeutic treatment of a muscular energetic deficiency, a state of asthenia and muscle fatigue or a state of heart fatigue and post-infarct condition.

Toxicology tests Both the carnitines and creatinol-phophate are products known for their low toxicity and good tolerability.

In tests performed in rats, doses of L-carnitine and creationol-phosphate in combination, corresponding to 250 mg/kg of each compound, were
4 administered intraperitoneally without the occurrence of any signs of toxicity. Likewise, no signs of toxicity were detected when 750 mg/kg of L-carnitine were administered orally in combination with 750 mg/kg of creatinol-phosphate. Even prolonged oral administration for one month of 200 mg/kg of L-carnitine plus 200 mg/kg of creatinol-phosphate to rats did not cause any toxic intolerance reaction. Full blood counts and blood-chemistry tests performed at the end of treatment also failed to reveal any abnormalities worthy of note as compared to controls. At autopsy, none of the main organs showed any signs of distress.
Histological and histochemical investigations confirmed these findings, the results being comparable to those obtained in the control animals.
Muscle fatigue test The method described by Zheng (Zheng R.L., Acta Pharmacol. Sinica, 14, 47, 1993) was used for this test in order to observe whether the administration of L-carnitine or creatinol-phosphate or of the two products in combination might increase reaction time in treated animals as compared to controls.

In this test, different groups of mice received daily oral doses of 200 mg/kg of L-carnitine or 200 mg/kg of creatinol-phosphate or of the two compounds in combination over the 6-day period preceding the test.
The animals were immersed in a tank full of water and swimming endurance time was measured.

Both L-carnitine and creatinol-phosphate increased swimming endurance time, but the greatest effect was observed in mice treated with the L-carnitine plus creatinol-phosphate combination. In these latter animals, in fact, swimming endurance time was significantly longer compared to controls, thus confirming the synergistic effect exerted by the components of the composition (see Table 1).

Table 1 Muscle fatigue tes .

Treatment Swimming time (min) Controls 93 8 L-carnitine 118 14 Creatinol-phosphate 124 11 L-carnitine + creatinol-phosphate 191 19 Forced muscular exercise test As is known, forced muscular exercise can produce structural- and inflammatory-type lesions at muscle fibre level, due to the increased oxygen consumption and to production of reactive oxygen species (ROS). A marker of the level of ROS-induced lipid peroxidation of the muscle may be obtained from its malondialdehyde (MDA) concentration. For this test, the method described by Husain was used (Husain K., Pathophysiology, 4, 69, 1997) as modified by Li (Li J.X., Acta Pharmacologica Sinica, 20, 126, 1999) which consists essentially in examining rats on a treadmill at controlled belt speed and preset inclination. In this way the rats were made to run at a belt speed of 28 m/min and an inclination of approximately 5 . Exhaustion of the control animals subjected to the exercise occurred after approximately 90 minutes.

The test was performed on rats receiving daily oral treament over the 6-day period preceding the test with 200 mg/kg of L-carnitine or with 200 mg/kg of creatinol-phosphate or with the two compounds in combination.

Five minutes and 30 minutes, respectively, after the end of the test, the animals were sacrificed and samples of gastrocnemius muscle were taken for measurement of the malondialdehyde (MDA) content using the reaction with thiobarbituric acid according to the method described by Ohkawa (Ohkawa H., Anal. Biochem., 95, 351, 1979).

The results of this test are illustrated in Table 2, which show that the combination of L-carnitine plus creatinol-phosphate induces a highly significant and unexpected reduction in the MDA concentration present in the muscle samples. This demonstrates the unexpected synergistic effect of L-carnitine and creatinol-phosphate in protecting muscle against damages induced by the reactive oxygen species (ROS) produced in the course of forced muscular exercise.

Table 2 Forced muscular x r is st Treatment MDA content in muscle (nmol.g-1) After 5 min After 30 min Controls 240 4 236 10 L-carnitine 218 11 216 14 Creatinol-phosphate 206 16 209 12 L-carnitine + creatinol-phosphate 163 14 169 19 Tests of ATP content in rabbit papillary muscle after hypoxia By submitting sections of rabbit papillary muscle to hypoxia a reduction in muscular ATP content can be induced. The presence in perfusion fluid of substances which interact in muscular energy metabolism may limit the hypoxia-induced loss of ATP content in muscle.

For this test a group of New Zealand rabbits were used. The rabbits received intravenous administrations of 100 mg/kg of L-carnitine or 100 mg/kg of creatinol-phosphate or the two compounds in combination every day over the 3-day period preceding the test. After the third day of treatment, all animals, including control animals, were sacrificed.

After removing the hearts, sections of papillary muscle measuring 1 mm in diameter and 4-5 cm in thickness were isolated. These tissue sections were perfused in a thermostatic bath with a 100% 02-saturated solution. On introducing 100% N2 into the bath instead of the 02, hypoxia was induced and maintained for the duration of 90 minutes. The tissues were then maintained in conditions of normal perfusion for a further period of 90 minutes. The ATP content of the papillary muscle was estimated according to the method described by Strehler (Strehler B.L., Methods in Enzymology III, N.Y. Acad. Press, 871, 1957.

The results of this test are presented in Table 3, which shows that the combination of L-carnitine plus creatinol-phosphate unexpectedly affords a surprisingly greater degree of protection against the ATP
reduction in papillary muscle subjected to hypoxia than does L-carnitine and creatinol-phosphate alone, thus demonstrating the synergistic effect of the two compounds present in the composition.

Table 3 Test of ATP content of rabbit pap llarv muscle Treatment ATP concentration (moUg tissue) Before hypoxia After hypoxia Controls 1.49 0.29 0.39 0.046 L-carnitine 1.53 0.15 0.48 0.036 Creatinol-phosphate 1.55 0.31 0.68 0.045 L-carnitine + creatinol-phosphate 1.60 0.28 1.18 0.051 Illustrative, non-limiting examples of compositions according to the invention are reported hereinbelow.

1) L-carnitine 400 mg Creatinol-phosphate 400 mg 2) Acetyl L-carnitine 300 mg Creatinol-phosphate 300 mg 3) Carnitine mixture 300 mg (L-carnitine 100 mg, acetyl L-carnitine 100 mg, propionyl L-carnitine 100 mg) Creatinol-phosphate 300 mg 4) L-carnitine 200 mg Creatinol-phosphate 200 mg Creatine 100 mg Taurine 50 mg Inosine 50 mg Coenzyme Qio 25 mg Selenium methionine 50 gg Vitamin E 5 mg Beta-carotene 5 mg
5) L-carnitine 100 mg Creatinol-phosphate 100 mg Phosphocreatinine 100 mg Creatine 100 mg Inosine 100 mg Vitamin C 50 mg Vitamin E 5 mg Beta-carotene 5 mg Coenzyme Qio 25 mg
6) L-carnitine 200 mg Creatinol-phosphate 200 mg Fructose- 1,6-diphosphate 200 mg Maltodextrin 200 mg Magnesium 10 mg Selenium methionine 50 g Zinc 10 mg Manganese 1 mg Coenzyme Qio 25 mg
7) L-carnitine 500 mg Creatinol-phosphate 500 mg Creatine 500 mg Coenzyme Qio 50 mg Vitamin E 10 mg Vitamin C 100 mg Beta-carotene 5 mg Magnesium 10 mg What is meant by pharmacologically acceptable salt of L-carnitine or alkanoyl L-carnitine is any salt of these active ingredients with an acid that does not give rise to unwanted toxic or side effects. Such salts are well known to pharmacy experts.

Examples of suitable salts, though not exclusively these, are: chloride;
bromide; iodide; aspartate, acid aspartate; citrate, acid citrate;
tartrate; phosphate, acid phosphate; fumarate; acid fumarate;
glycerophosphate; glucose phosphate; lactate; maleate, acid maleate;
orotate; oxalate, acid oxalate; sulphate, acid sulphate, trichloroacetate, trifluoroacetate and methanesulphonate.

A list of FDA-approved pharmacologically acceptable salts is given in Int. J. of Pharm. 33, (1986), 201-217.

Claims (9)

CLAIMS:
1. An oral, parenteral, rectal or transdermal composition, which comprises:

(a) at least one of L-carnitine, acetyl L-carnitine, propionyl L-carnitine, butyryl L-carnitine, valeryl L-carnitine or isovaleryl L-carnitine, or a pharmacologically acceptable salt thereof; and (b) creatinol-phosphate or a pharmacologically acceptable salt thereof.
2. The composition of claim 1, wherein the weight ratio (a):(b) is from 1:0.1 to 1:1.
3. The composition of claim 1 or 2, wherein the pharmacologically acceptable salt of component (a) is chloride, bromide, iodide, aspartate, acid aspartate, citrate, acid citrate, tartrate, phosphate, acid phosphate, fumarate, acid fumarate, glycerophosphate, glucose phosphate, lactate, maleate, acid maleate, orotate, acid oxalate, sulphate, acid sulphate, trichloroacetate, trifluoroacetate or methane sulphonate.
4. Use of the composition of any one of claims 1 to 3, for preparing a dietary supplement for the prevention of a muscular energetic deficiency, a state of asthenia and muscle fatigue, or a state of heart fatigue and post-infarct condition or for enhancing a sporting performance.
5. Use of the composition of any one of claims 1 to 3, for preparing a medicament for the therapeutic treatment of a muscular energetic deficiency, a state of asthenia and muscle fatigue or a state of heart fatigue and post-infarct condition.
6. Use of the composition of any one of claims 1 to 3, for the therapeutic treatment of a muscular energetic deficiency, a state of asthenia and muscle fatigue or a state of heart fatigue and post-infarct condition.
7. The composition of any one of claims 1 to 3, for use in preparing a medicament for the therapeutic treatment of a muscular energetic deficiency, a state of asthenia and muscle fatigue or a state of heart fatigue and post-infarct condition.
8. The composition of any one of claims 1 to 3, for use in the therapeutic treatment of a muscular energetic deficiency, a state of asthenia and muscle fatigue or a state of heart fatigue and post-infarct condition.
9. A commercial package comprising the composition of any one of claims 1 to 3, and associated therewith instructions for the use thereof in the therapeutic treatment of a muscular energetic deficiency, a state of asthenia and muscle fatigue or a state of heart fatigue and post-infarct condition.
CA002377128A 1999-07-23 2000-07-21 Composition for the prevention of muscle fatigue and skeletal muscle adaptation to strenuous exercise Expired - Lifetime CA2377128C (en)

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IT1999RM000467A IT1306173B1 (en) 1999-07-23 1999-07-23 COMPOSITION FOR THE PREVENTION OF MUSCLE FATIGUE AND TO IMPROVE THE MUSCLE ENERGY PERFORMANCE.
ITRM99A000467 1999-07-23
PCT/IT2000/000308 WO2001006873A1 (en) 1999-07-23 2000-07-21 Composition for the prevention of muscle fatigue and skeletal muscle adaptation to strenuous exercise

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HUP0202298A2 (en) 2002-10-28
IL147408A0 (en) 2002-08-14
DK1196046T3 (en) 2004-08-02
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EP1196046A1 (en) 2002-04-17
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ES2216931T3 (en) 2004-11-01
HUP0202298A3 (en) 2005-07-28

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