HK1026124B - Nutritional supplement - Google Patents

Description

Nutritional supplement for promoting adaptation of skeletal muscle to strenuous exercise and for combating asthenic individuals

The present invention relates to a nutritional supplement comprising, as an essential active ingredient, a mixture of "carnitines", wherein "carnitines" refers to the first of L-carnitine and the series of lower (short-chain) fatty acyl L-carnitines, or their pharmacologically acceptable salts.

The nutritional supplement is particularly suitable for regulating the adaptation of the skeletal muscles and the liver of individuals participating in intense, sustained physical activity, but also for counteracting the feelings of muscular fatigue and fatigue that physically weak persons exhibit even without any kind of more or less intense physical activity.

Persons participating in sports activities, whether as professionals or as amateurs, wish to maximally adapt the skeletal muscles to the ability to support prolonged intense physical activity over a relatively short period of time and to maintain this ability for as long a period as possible. Seeking such an optimum degree of physical fitness may lead to abuse of drugs, particularly steroid drugs. It is well known that such drugs can increase protein synthesis, thereby enhancing muscle mass growth to a greater extent than can be achieved by training and diet. However, the use of these drugs is certainly harmful and illegal in the field of professional sports.

It is therefore clear that the only way to achieve the above object correctly is the combination of a suitable training schedule with a suitable diet fortified with suitable nutritional supplements.

Frailty means a diffuse group of specific symptoms representing today's stress conditions, particularly prevalent in metropolitan areas and affecting a large population, mostly independent of factors of age and social condition, characterized by insufficient or lost muscle strength, tiredness, fatigability, inadequate response to stimuli.

It is an object of the present invention to provide a nutritional supplement which can be used by consumers of the above type.

The mitochondrial matrix is the site of oxidation of long chain fatty acids, and L-carnitine plays a uniquely important physiological role as a carrier of long chain fatty acids across the inner mitochondrial membrane into the mitochondrial matrix, which has been discovered for decades since this basic principle was discovered (fritzi.b.: metabolic consequences of carnitine on the oxidative effects of long chain fatty acids, as reported in "control of cellular compartmentalization and fatty acid metabolism", f.c. gran, new york, academy press, 1968, pages 39-63). Since the first confirmation (Engel and Angelini, science, 1973, 179: 899-.

Carnitine is present in all biological tissues in a rather high concentration in the form of free carnitine and in a lower concentration in the form of fatty acyl carnitine, which is a metabolite of the following reversible reactions:

acyl-coenzyme A + carnitineAcyl carnitine + CoASH the reaction is catalyzed by three groups of enzymes, which are transferases, distinguished mainly by their specificity for the reaction substrate: the group of Carnitine Acetyl Transferases (CAT) with short-chain acyl groups (such as acetyl and propionyl) as substrates, the group of Carnitine Octanoyl Transferases (COT) with medium-chain acyl groups as substrates, and the group of Carnitine Palmitoyl Transferases (CPT) with long-chain acyl groups as substrates.

The important role of carnitine in intermediary metabolism, particularly in terms of its limited biosynthesis, may explain how carnitine deficiency may occur as a secondary event in pathological functions involving different organs and devices. The broadening of the clinical spectrum has been accompanied by an increase in the number of therapeutic opportunities associated with the efficacy of this naturally occurring compound: the observation that replacement therapy with L-carnitine reversed the significant clinical manifestations in patients with lipid storage myopathy shows its potential efficacy in all respects. The U.S. Food and Drug Administration (FDA) has not only given L-carnitine the status of an isolated drug, but also has placed it on the list of life-saving drugs.

In line with our deeper understanding of the pathological relationships involving primary and secondary carnitine deficiencies, there have emerged scientific and patent publications that are impressive, primarily directed at L-carnitine, and to a substantially lesser extent, at a large number of fatty acyl carnitines.

Let us review this situation in part. It has been suggested that in the cardiovascular field, L-carnitine can be used for the treatment of cardiac arrhythmias and congestive heart failure (US4,656,191), myocardial ischemia and hypoxia (US4,649,159); in the treatment of lipid metabolism diseases, it can be used for treating hyperlipidemia and hyperlipoproteinemia (US4,315,944), and normalizing abnormal ratio of HDL to LDL + VLDL (US4,255,449); can be used in the field of total parenteral nutrition (US4,254,147 and 4,320,145); nephrology, it is used to combat the onset of muscle weakness and muscle spasms caused by the loss of carnitine in the dialysate of chronic uremic patients undergoing regular hemodialysis treatment (US4,272,549); against the toxic effects caused by anticancer agents, such as doxorubicin (US4,400,371 and US4,713,379), and halogen-containing anesthetics, such as haloalkanes (US4,780,308); for the treatment of venous stasis (US4,415,589); fighting the deterioration of many biochemical and behavioral parameters in elderly patients (US4,474,812); for normalization of triglyceride and Tumor Necrosis Factor (TNF) levels in AIDS patients and asymptomatic HIV-seropositive patients (US5,631,288).

L-carnitine has also been proposed for use in combination with other active ingredients, such as L-carnitine plus coenzyme Q10, with a broader metabolic/anti-atherosclerotic activity spectrum (US4,599,232).

As regards the acylcarnitines, it is well known that acetyl L-carnitine is useful in the treatment of diseases of the central nervous system, in particular Alzheimer's disease (US4,346,107), in the treatment of diabetic neuropathy (US4,751,242), while propionyl L-carnitine has been proposed for the treatment of peripheral vascular disease (US4,343,816) and congestive heart failure (US4,194,006).

Although the above patent is described in a concise and partial manner, it is clear that L-carnitine is of significantly greater portion and importance than its fatty acyl derivatives.

Analysis of the patent literature indicates that in some cases the effects of L-carnitine and some lower acyl carnitines are equivalent for a given indication. A deeper examination of this equivalence finds it more in the interest of patenting motivation to obtain the broadest scope of protection than results from appropriate pharmacological/clinical studies. The above-described reversible equilibrium reaction between carnitine and fatty acyl-carnitine probably also reveals an "equivalence" of this behavior.

It can also be seen from an examination of the scientific and patent literature that the attention of researchers has always been focused specifically on the individual carnitines, as already said, mainly on L-carnitine. This results in a single compound culture, which is, in fact, a technical prejudice that has hampered the study of the efficacy of the "carnitine" mixture. In fact, there is no evidence that mixtures containing L-carnitine, acetyl L-carnitine and propionyl L-carnitine (or their pharmacologically acceptable salts) have been suggested as essential active ingredients for therapeutic or nutritional purposes. It is clear that any mixture wherein L-carnitine, acetyl L-carnitine and propionyl L-carnitine are present in well-defined weight ratios (as will be described in detail hereinafter) has never been disclosed before. This weight ratio is critical in order to obtain the desired therapeutic/nutritional effect.

It has now been found that a mixture of L-carnitine, acetyl L-carnitine and propionyl L-carnitine (or the pharmacologically acceptable salts thereof) produces an unexpectedly strong synergistic effect compared to the single "carnitine", which has been demonstrated in various tests. In these tests, the efficacy of a mixture of L-carnitine, acetyl L-carnitine and propionyl L-carnitine was compared with the efficacy of their individual administration.

The combined action of these three "carnitines" can affect the fatty acid glycolysis and oxidation pathways, which is not surprising. Also, the presence of propionyl L-carnitine, a substance that increases the concentration of succinyl-coa in the tricarboxylic acid cycle (anaplerotic effect), increases its overall speed. Obviously, this increase in speed can be promoted by the addition of sufficient acetyl units. This latter effect is accomplished by acetyl L-carnitine. Indeed, due to the presence of mitochondrial carnitine acetyltransferase, the acetyl group of acetyl L-carnitine can be transferred to coenzyme a to synthesize acetyl coenzyme a, a key compound in the tricarboxylic acid cycle. Finally, carnitine enhances the oxidation of fatty acids themselves through its known role of transferring fatty acids into the mitochondrial matrix. Most of the energy required for the muscle contraction process is extracted from the fatty acids.

However, these obvious reasons are at best thought of as the "additive" effect of the mixture of "carnitines", rather than the surprising, significant synergistic effect, which is manifested as an enhancement in ATP yield as shown in clinical studies which will be detailed below. ATP is the main energy source of the cell.

As a result of studies that make it possible to determine this synergistic effect, the present invention provides a nutritional supplement comprising the following combinations: (a) l-carnitine; (b) acetyl L-carnitine; (c) propionyl L-carnitine; or a pharmacologically acceptable salt thereof; and a pharmacologically acceptable excipient. (a) The weight ratio of (b) to (c) ranges from 1: 1 to 1: 0.1, wherein the aforementioned weight ratios refer to L-carnitine, acetyl L-carnitine and propionyl L-carnitine expressed as internal salts.

It has also been found that, in addition to the essential components of the mixture (L-carnitine, acetyl L-carnitine and propionyl L-carnitine or the pharmacologically acceptable salts thereof), the nutritional supplement of the invention may advantageously comprise further fatty acyl L-carnitines, such as isovaleryl L-carnitine, essential amino acids or mixtures thereof and creatine and/or phosphocreatine.

The weight ratio of L-carnitine, acetyl L-carnitine, propionyl L-carnitine and isovaleryl L-carnitine is in the range of 1: 1 to 1: 0.1, preferably 1: 0.5.

All amino acids, whether essential or non-essential, are substrates required by muscle cells for protein synthesis. It is well known that excess amino acids and other macromolecules beyond those required for protein synthesis cannot be excreted nor stored, unlike fatty acids and glucose. On the other hand, an excess of amino acids is used as an energy substance. When the alpha-amino group is removed, the remaining carbon skeleton is converted to a basic metabolic intermediate. Most of the amino groups of these excess amino acids are converted to urea, while the carbon skeleton is converted to acetyl-coa, acetoacetyl-coa, pyruvate or one of the intermediates of the citric acid cycle. Thus, fatty acids, ketone bodies and glucose are formed from these amino acids.

Preferably, the essential amino acids or mixtures thereof include the branched chain amino acids valine, leucine and isoleucine or mixtures thereof. Wherein the weight ratio of the mixture of L-carnitine, acetyl L-carnitine, propionyl L-carnitine and essential amino acid or mixture thereof is 3: 1 to 1: 1.

The nutritional supplement of the present invention may also advantageously contain non-essential amino acids, in particular glutamine, L-glutamic acid, L-aspartic acid and L-asparagine.

One example of a nutritional supplement of the present invention comprises: 40% to 60% by weight of a mixture of L-carnitine, acetyl L-carnitine, propionyl L-carnitine or their pharmacologically acceptable salts; (ii) 10% to 15% by weight of valine;

10% to 15% by weight leucine;

10% to 15% by weight of isoleucine; and (iii) 8% to 12% by weight of creatine or phosphocreatine.

If present, the nonessential amino acids will comprise 10% to 30% by weight of the nutritional supplement.

For all the efficacies and purposes of the present invention, L-carnitine, acetyl L-carnitine, propionyl L-carnitine and isovaleryl L-carnitine refer to these compounds in the form of their inner salts.

Pharmacologically acceptable salts of L-carnitine, acetyl L-carnitine, propionyl L-carnitine or isovaleryl L-carnitine, refers to any salt of such carnitine with an acid that does not produce unwanted toxicity or side effects. These acids are well known to pharmacologists and to pharmaceutical experts.

Non-limiting examples of such salts are: a chloride; bromide; an iodide; a salt of aspartic acid; an acid aspartate; a citrate salt; an acid citrate salt; a tartrate salt; a phosphate salt; an acid phosphate; fumarate; an acid fumarate; a glycerophosphate salt; glucose phosphate; a lactate salt; a malate salt; an acid malate salt; orotate salts; an oxalate salt; an acid oxalate; a sulfate salt; acid sulfate; trichloroacetate salt; trifluoroacetate and methanesulfonate.

The list of FDA-approved pharmacologically acceptable salts is listed on page 201-217 of the International journal of pharmacy 33 (1986); this publication is incorporated herein by reference.

Fumarate is particularly preferred, for example, L-carnitine fumarate exerts a double protective effect on protein metabolism; it indirectly stimulates the biosynthesis of proteins by a direct increase in intermediary metabolism, while it induces a sparing/protective effect on the muscle protein component as a result of fatty acid transfer.

Both strenuous exercise and infirm individuals can achieve the best results by taking the following: about 500 mg/day L-carnitine, 50-500 mg/day acetyl L-carnitine and 50-500 mg/day propionyl L-carnitine, or their equivalent weights of pharmacologically acceptable salts.

The nutritional supplement may also contain inorganic salts such as disodium citrate, monopotassium phosphate, calcium lactate and magnesium taurate.

The nutritional supplement of the present invention is suitable for oral administration.

The nutritional supplement must not be used as the sole or primary source of nutrition on a daily basis.

Thus, the supplemental portion of the diet will include the appropriate amino acids, carbohydrates, fats, vitamins and minerals.

The daily intake of the nutritional supplement may vary within wide limits, depending on, for example, the age and weight of the user, as well as the strength and complexity of the training programme, or, as the case may be, the physical exercise undertaken by the user. In general, however, the amount of protein ingested from the nutritional supplement should not exceed 30-35% by weight of the total amount of protein normally ingested by the user per day.

The rational long-term use of the nutritional supplement of the present invention results in the following positive effects: (a) can preserve the branched-chain amino acids present in muscle proteins, particularly skeletal muscle; (b) stimulation of protein synthesis in skeletal muscle and liver; (c) can obtain amino for synthesizing alanine and glutamine, both of which participate in gluconeogenesis; (d) promoting metabolic conversion of pyruvate to alanine rather than lactate; and (e) promoting the flux of hydrogen ions from the skeletal muscle via the conversion of glutamate to glutamine to maintain an optimal intramuscular pH.

One non-limiting example of a nutritional supplement of the present invention is given below. The composition is suitably dissolved in a sufficient amount of water, such as 200 and 300ml of water, and is suitable for oral administration in liquid form. Daily dose of the basic active ingredient-fumaric acid L-carnitine 200mg

(=143mg L-carnitine inner salt) -acetyl L-carnitine 75 mg-propionyl-carnitine 75mg branched amino acid and the non-essential amino acid-isoleucine 50 mg-leucine 50 mg-valine 50 mg-aspartic acid 150 mg-glutamic acid 200 mg-asparagine 100mg creatine phosphate 50mg vitamin-vitamin C250 mg inorganic salt-disodium citrate (=7.8mg sodium) 40 mg-monopotassium phosphate (=8.6mg potassium) 30 mg-calcium lactate (=20mg calcium) 110 mg-magnesium taurate (=73.0mg magnesium) 820mg total active ingredient 2250 mg-excipient 2750mg total weight 5000mg total weight 5000mg

It is obvious to the pharmaceutical specialist that the compositions of the present invention can be formulated into solid forms, by using suitable excipients, to make tablets, chewable tablets, capsules and the like.

Numerous studies, presented below, demonstrate that mixtures of L-carnitine, acetyl L-carnitine and propionyl L-carnitine act synergistically compared to the L-carnitine, acetyl L-carnitine and propionyl L-carnitine used alone. Effect of the mixture on Athletic Performance

To evaluate the effect of their mixture (C0MB) on the performance of endurance athletes (study 1) and subjects on non-stressed, recreational physical exercise (study 2) compared to L-carnitine, acetyl L-carnitine and propionyl L-carnitine taken alone, two studies were carried out. Study 1

The crowd: 40 healthy male volunteers who had been engaged in long distance runs (e.g., marathon) for at least 4 years.

Research and design: randomized, double-blind, parallel, placebo-controlled, period 45 days.

Including the following standards: -sex: male-age: 20-40 years-weight: no more than 10% of normal body weight-respiratory exchange rate: 0.8

Exclusion criteria: gastrointestinal, cardiovascular, skeletal and nervous system disorders renal and hepatic insufficiency

All subjects were not subjected to abnormal physical and nutritional stress during the study. Treatment of

To ensure blindness of the study, all subjects orally took 6 tablets per day (2 × 3, after meal). Study design was achieved by varying the number of active and placebo tablets taken per treatment group. This change depends on the particular substance to be administered, as follows: -8 subjects, taking 1.5g COMB (3 × 500mg tablets, each tablet consisting of 167mg lc, 167mg PLC and 167mg ALC, +3 placebo) daily for 45 days; -8 subjects, taking 2g L-carnitine (LC) daily (4 x 500mg tablets +2 placebo tablets) for 45 days; 8 subjects, taking 2.5g propionyl L-carnitine (PLC) (5X 500mg tablet +1 placebo) daily for 45 days; -8 subjects, taking 3g acetyl L-carnitine (ALC) (6 x 500mg tablets) daily for 45 days; 8 subjects, taking placebo (PLA,6 tablets) daily for 45 days.

The athlete's weekly training distance was required to remain relatively constant during the study. Evaluation of efficacy: after each athlete had completed a progressive treadmill test (gradient 0 °) until exhaustion, the respective oxygen consumption was recorded (V0)₂M 1/min) and treadmill running speed peak (km/hour). The initial running speed of the athlete is 8 km/h, and the running speed is increased by 2 km/h every 3 minutes until the running speed is up toReaching 16 km/h. Thereafter, the rate was increased by 1 km/hour every 2 minutes until the physical strength was exhausted, which had two measurement criteria: 1-VO₂Stabilizing; 2-respiratory exchange rate over 1.1. The treadmill peak was the highest running speed that the athlete could achieve during the test, lasting 60 seconds.

All subjects were at baseline (T)₀) And 45 days after treatment (T)₄₅) Evaluation was performed. In addition, blood chemistry and urine parameters were measured to monitor negative effects.

Data, including factors such as subject, time, and treatment, were analyzed using analysis of variance (ANOVA). Differences in scores between different treatment groups were assessed using the t-test. The significance is P < 0.05. Results

The physical characteristics of the athlete are as follows: age (year) 27.5 ± 3.8; height (cm) 175 +/-6.5; body weight (Kg)69.9+ 7. The results regarding the efficacy parameters are as follows:

group (n =8)	Maximum running speed (km/h)		VO2(ml/min)
						T0	T45	T0	T45
PLA	19.7±0.7	20.1±0.8	3108.7±325.4	3071.2±245.4
					COMB	19.6±0.7	23.0±0.7*$°^	3025.0±110.2	2551.2±146.5*°^
LC	19.5±0.9	21.4±0.7*°	2916.2±166.7	2850.0±119.5
					ALC	19.6±0.7	20.0±0.7^	2950.6±96.0	2685.0±105.1*
PLC	19.6±0.7	21.5±0.5*	2953.1±97.3	2907.5±115.0

Data mean ± standard error compared to PLA, P < 0.05; p is less than 0.05 compared with LC; p is less than 0.05 when compared with ALC; p is less than 0.05 compared with PLC.

At T₀There were no statistically significant differences between treatment groups.

At T₄₅The highest running speed of the COMB group was significantly higher than the other groups, but not accompanied by VO₂Is increased.

Thus, it is clear that treatment with COMB positively affects physical performance of durable athletes.

No negative effects were reported.

Study 2

The crowd: 40 healthy volunteers (23 males and 17 females) engaged in non-stressful, recreational physical exercise.

Research and design: randomized, double-blind, parallel, placebo-controlled, period of 15 days.

Including the following standards: -sex: male and female-age: 18-40 years-weight: no more than 10% of normal body weight-respiratory exchange rate: 0.8

Exclusion criteria: gastrointestinal, cardiovascular, skeletal and nervous system disorders renal and hepatic insufficiency

All subjects were not subjected to abnormal physical and nutritional stress during the study. Treatment of

To ensure blindness of the study, all subjects orally took 6 tablets per day (2 × 3, after meal). Study design was achieved by varying the number of active and placebo tablets taken per treatment group. This change depends on the particular substance to be administered, as follows: -8 subjects, taking 1.5g COMB (3 × 500mg tablets, each tablet comprising 167mg lc, 167mg PLC and 167mg ALC, +3 placebo) daily for 15 days; -8 subjects, taking 2g L-carnitine (LC) daily (4 x 500mg tablets +2 placebo tablets) for 15 days; 8 subjects, taking 2.5g propionyl L-carnitine (PLC) (5X 500mg tablet +1 placebo) daily for 15 days; -8 subjects, taking 3g acetyl L-carnitine (ALC) (6 x 500mg tablets) daily for 15 days; 8 subjects, taking placebo (PLA,6 tablets) daily for 15 days.

And (3) evaluating the efficacy: measurement of maximum oxygen consumption (VO)_2maxMl/kg/min) and total workload (kgm/hr) to evaluate treatment efficacy.

At baseline (T)₀) And 15 days after treatment (T)₁₅) The maximum dynamic vital capacity (ergometric effort) test (triangle treadmill) was performed on all subjects, the workload was determined according to the Bruce protocol (7 steps per 3 minutes, 10-22% inclination, speed 1.7-6.5 Mph).

In addition, blood chemistry and urine parameters were measured to monitor negative effects.

Data, including factors such as subject, time, and treatment, were analyzed using analysis of variance (ANOVA). Differences in scores between treatment groups were assessed using the t-test. The significance is P < 0.05. Results

The physical characteristics of the subject were: age (year of age) 29 ± 5.1; body weight (Kg)74 + -5.2; height (cm) 174.5 + -6.8.

The results regarding the efficacy parameters are as follows:

group (n =8)	Total work load (kgm/hour)		VO2max(ml/kg/min)
						T0	T15	T0	T15
PLA	9600.9±1600.4	9800.4±910.0	62.1±4.9	61.8±4.4
					COMB	10390.2±1400.5	13280.5±700.1*$°	61.5±4.3	75.9±3.3*$°^
LC	10200.5±1510.1	11400.2±700.2*	60.6±4.2	67.5±2.5
					ALC	10020.5±1500.2	11100.4±1100.8	61.7±5.1	64.4±4.9
PLC	10800.2±10015.9	12100±900.4*	62.6±4.8	69.0±3.0*

Data mean ± standard error compared to PLA, P < 0.05; p is less than 0.05 compared with LC; p is less than 0.05 when compared with ALC; p is less than 0.05 compared with PLC.

At T₀There were no statistically significant differences between groups.

At T₁₅The total workload was significantly higher for the COMB group than for the PLA, LC and ALC groups. And, VO_2maxSignificantly higher than the other groups. As a result, subjects treated with COMB had more effective physical performance.

No negative effects were reported. Effect of the mixture on Weak individuals

The aim of this study was to evaluate the effect of the mixture of L-carnitine, acetyl L-carnitine and propionyl L-Carnitine (COMB) on frail individuals compared to the use of L-carnitine, acetyl L-carnitine and propionyl L-carnitine alone.

The study was designed as a randomized, double-blind, parallel group comparison between COMB and L-carnitine or acetyl L-carnitine or propionyl L-carnitine or placebo for a period of 30 days.

The subjects of the study were males or females between 18 and 60 years of age, who were post-operative (n =19) and debilitating with infectious disease (n =15) as well as "idiopathic" debilitation (n = 26). Exclusion criteria included history of cardiovascular, skeletal and nervous system disease, liver and kidney insufficiency, and depression (diagnosed with the Beck depression table).

Consent was obtained from all subjects prior to starting the trial. Treatment of

To ensure blindness of the study, all subjects took 6 tablets per day (2 × 3, after meal). Study design was achieved by varying the number of active and placebo tablets taken for each treatment group. This change depends on the particular substance to be administered, as follows: 12 subjects, taking 1.5g COMB (3X 500mg tablets, each tablet containing 167mg LC, 167mg PLC and 167mg ALC, +3 placebo) daily for 30 days; 12 subjects, taking 2g L-carnitine (LC) daily (4 × 500mg tablets +2 placebo tablets) for 30 days; 12 subjects, taking 2.5g propionyl L-carnitine (PLC) (5X 500mg tablet +1 placebo) daily for 30 days; -12 subjects, taking 3g acetyl L-carnitine (ALC) (6 x 500mg tablets) daily for 30 days; 12 subjects, taking placebo (PLA,6 tablets) daily for 30 days.

And (3) evaluating the efficacy: at baseline (T)₀) And 30 days after treatment (T)₃₀) Then, 20 self-reported evaluation tables (MFI-20 table, Smets e.m.a. et al, journal of physical and mental research 39: 315-325, 1995; british journal of cancer 73: 241-. The evaluation chart includes fatigue in general, physical fatigue, decreased vitality, decreased motivation, and mental fatigue. A total score of between 20 and 40 indicates the absence of frailty, and above 40 (up to a maximum of 100) indicates the progressive severity of frailty.

Data were analyzed by analysis of variance (ANOVA). Differences in scores between treatment groups were assessed using the t-test. The significance is P < 0.05. Results

The following results were obtained:

group (n =12)	MFI-20 Table score
				T0	T30
PLA	73.2±2.5	74.0±3.5
			COMB	70.4±4.1	24.2±2.2*$°^
LC	75.2±6.2	52.5±4.7*°^
			ALC	69.8±7.1	39.4±5.5*
PLC	70.9±6.0	65.2±6.6*

Data mean ± standard error compared to PLA, P < 0.05; p is less than 0.05 compared with LC; p is less than 0.05 when compared with ALC; p is less than 0.05 compared with PLC.

At T₀There were no significant differences between treatment groups.

At T₃₀At that time, subjects in the COMB group had recovered from weakness. Subjects in the LC, PLC and ALC groups had significantly lower mean scores than those in the placebo group, but only subjects in the ALC group achieved a generally normal mean.

Claims (10)

1. A nutritional supplement comprising a mixture of:

(a) l-carnitine;

(b) acetyl L-carnitine;

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

wherein the weight ratio of (a) to (b) to (c) is from 1: 1 to 1: 0.1, and the substances are both in the form of internal salts.

2. The nutritional supplement of claim 1, further comprising:

(d) isovaleryl L-carnitine or a pharmacologically acceptable salt thereof in the form of an inner salt, wherein the weight ratio of (a) to (b) to (c) to (d) is from 1: 1 to 1: 0.1.

3. A nutritional supplement as claimed in claim 1 or 2, further comprising essential amino acids or mixtures thereof.

4. The nutritional supplement of claim 3, wherein the essential amino acids are branched chain amino acids and are selected from valine, leucine, and isoleucine, or mixtures thereof.

5. The nutritional supplement of claim 3, wherein the weight ratio of the mixture of L-carnitine, acetyl L-carnitine, propionyl L-carnitine and the essential amino acid or mixture thereof is from 3: 1 to 1: 1.

6. The nutritional supplement of claim 3, further comprising glutamine, L-glutamic acid, L-aspartic acid, and L-asparagine.

7. The nutritional supplement of claim 3, further comprising creatine selected from the group consisting of creatine and phosphocreatine.

8. A nutritional supplement as claimed in claim 3, comprising:

40 to 60% by weight of a mixture of L-carnitine, acetyl L-carnitine and propionyl L-carnitine or the pharmacologically acceptable salts thereof;

(ii) 10% to 15% by weight of valine;

10% to 15% by weight leucine;

10% to 15% by weight of isoleucine; and

(iii) 8% to 12% by weight of creatine or phosphocreatine.

9. The nutritional supplement of claim 8, further comprising from 10% to 30% by weight of non-essential amino acids.

10. A nutritional supplement as claimed in claim 1 or 2, wherein the pharmacologically acceptable salt is selected from: a chloride; bromide; an iodide; a salt of aspartic acid; an acid aspartate; a citrate salt; an acid citrate salt; a tartrate salt; a phosphate salt; fumarate; an acid fumarate; a glycerophosphate salt; glucose phosphate; a lactate salt; a malate salt; an acid malate salt; orotate salts; an oxalate salt; an acid oxalate; a sulfate salt; acid sulfate; trichloroacetate and methanesulfonate.