KR20010042765A - Composition comprising L-carnitine or an alkanoyl L-carnitine and NADH and/or NADPH - Google Patents

Abstract

The present invention relates to L-carnitine or alkanoyl L-carnitine or pharmacologically acceptable salts thereof and NADH, which are useful as food supplements and agents for treating chronic fatigue syndrome and Parkinson's disease, for individuals or vulnerable individuals engaged in strenuous physical activity. And / or a composition containing NADPH.

Description

Composition comprising L-carnitine or an alkanoyl L-carnitine and NADH and / or NADPH}, including L-carnitine or alkanoyl L-carnitine and NADH and / or NADPH.

Whether a professional or an amateur, a sportsman wants to achieve maximum adaptation of skeletal muscles that can sustain intense physical exertion for as short a time as possible. The pursuit of adequacy of physical adaptation attempts to abuse drugs, especially steroids. It is well known that these drugs can increase protein synthesis and consequently increase muscle size growth to a greater extent than can be obtained by training and diet. However, the use of such drugs is naturally illegal as well as harmful when done in the field of professional sports.

It is therefore evident that the only way to achieve the above mentioned objectives is to receive adequate training in conjunction with a suitable diet that has been enhanced with suitable food supplements.

Asthenia means the spread of certain symptoms that are typical of the stresses of life that affect a large group of people, especially those that are particularly widespread in today's metropolitan area, regardless of age and social conditions. And loss of muscle strength and fatigue that improperly respond to stimuli.

When used as a purely therapeutic substance, one particular application of the compositions according to the invention is to use in the treatment of syndromes similar to idiopathic Parkinson's disease due to the administration of chronic fatigue syndrome, Parkinson's disease and illegal drugs.

Chronic Fatigue Syndrome (CFS), first described in the Annals of Internal Medicine in 1988, is a disease characterized by the degree of fatigue, not explained by any known reason. Sometimes more severe than when faced with a very serious illness such as a tumor or AIDS, and lasting more than six months is more debilitating than causing a 50% reduction in work life and normal social relations.

According to standards outlined in the Diagnostics of Internal Medicine (Annals of Internal Medicine, 1994, December, 1994), chronic fatigue syndrome must be present if at least four of the following eight symptoms last for more than six months.

1. neuropsychic confusion such as memory loss, extreme anxiety, mental confusion, or difficulty in thinking;

2. pharyngitis;

3. Promotes and weakens the secretion of the neck or armpit lymph nodes;

4. muscle soreness;

5. Movable arthralgia without any swelling of the joints;

6. A headache that is specific to severe headaches and manifests itself in severe forms prior to illness;

7. Sleep disorders characterized by insomnia or excessive sleep or drowsiness;

8. Generalized fatigue and discomfort lasting 24 hours or more after physical activity at an easily tolerable level.

Since Parkinson's disease is generally regarded as an idiopathic condition, it is well known that the symptoms of Parkinsonism may be the result of drug abuse such as phenothiazine, butyrophenone, reserpin.

Recently, Parkinson's disease has been studied in drug abusers who inject themselves with a compound similar to meperidine, a compound that abuses the production of MPTP and MPPP.

In fact, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP or NMPTP) and 1-methyl-4-phenyl-propoxy-piperidine (MPPP) are found in the substantia nigra. It selectively destroys dopamine-sensitive neurons and induces the syndrome in both primates as well as humans with idiopathic Parkinson's disease as a whole, with its clinical, pathological and biochemical aspects and its pharmacological response.

The symptoms of idiopathic Parkinson's disease and MPTP-induced Parkinson's disease are so similar that Parkinson's disease has been assumed to "behave more than a model, and MPTP-induced Parkinson's disease may be a toxic source of Parkinson's disease." Burns et al. .: The neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in the monkey and man. Can. J. Neur. Sci., 11, n. 1 (supplement), 166-168, February 1984].

Selective treatments for the management of Parkinson's disease are currently based on the administration of levodopa (L-dopa), a dopamine metabolism precursor that, by itself, is unable to cross the blood-brain barrier.

Levo-dopa should be administered at very high doses, since levodopa is extensively metabolized before reaching the reaction site in the brain. Therefore, L-dopa is administered in combination with carbidopa, and the dopa decarboxylase inhibitor interferes with the metabolism of levodopa before the latter reaches the brain.

When levodopa is administered alone, side effects such as loss of appetite, nausea, vomiting and orthostatic hypotension may occur, but are substantially alleviated as soon as carbidopa is administered. However, even when combined with a decarboxylation inhibitor several months after treatment of L-dopa, other very difficult side effects such as facial, trunk, limb dyskinesia are possible and frequent. In most cases, these abnormalities indicate that the drug dose has reached a threshold that should not be exceeded.

Therefore, the strong need for adjuvant / prophylactic / treatment substances as a result of substantial non-toxic, side-effects is not only a simple requirement for adequate food supplementation, but also safe for many users to use in the early signs of symptoms under the above mentioned pathological conditions. Can be.

Various purposes such as adjuvant, prophylactic, pure therapeutic substances are obtained by the components of the invention, and as described in detail below, L-carnitine or low C2-C6 alkanoyl L-carnitine or their pharmacology as its basic components. It consists of a novel composition comprising an optionally acceptable salt and a reduced form of nicotinamide adenine dinucleotide (NADH) or a reduced form of NADH precursor and / or nicotinamide adenine dinucleotide phosphate (NADPH).

Fritz IB: The metabolic consequences of the effects of carnitine as a carrier of long-chain fatty acids across the inner mitochondrial matrix in the mitochondrial matrix where oxidation occurs. on long-chain fatty acid oxidation. In Cellular Compartmentalization and Control of Fatty Acid Metabolism. Edited by F. C. Gran, New York, Academic Press, 1968, pp. 39-63] After more than a few decades, after first discovering that major deficiencies in L-carnitine are a serious and sometimes fatal cause of myopathy (lipid storage myopathy) [Engel and Angelini, Science, 1973] , 179: 899-902], contrary to the pathological significance of major and secondary L-carnitine deficiencies, our knowledge of the therapeutic and nutritional value of external supply of carnitine has increased enormously.

Carnitine is present in all biological tissues in relatively high concentrations in the form of carnitine only and in the form of acyl carnitine, the metabolic product of the reversible reaction:

Acyl CoA + Carnitine ⇔ Acyl Carnitine + CoASH

It is catalyzed by three groups of enzymes, mainly transferases, distinguished by their specificity to the reaction substrate: carnitine acetyl transferase (CAT) groups having short-chain acyl groups (such as acetyl and propionyl) as substrates; Carnitine octanoyl transferase (COT) group having a heavy chain acyl group as a substrate; Carnitine palmitoyl transferase (CPT) group having a long chain acyl group as a substrate.

With regard to particularly limited biosynthesis, the important role of carnitine in intermediate metabolism explains how carnitine deficiency can occur as a secondary event in pathological function involving multiple organs. Expansion of clinical scope is undertaken by increasing therapeutic opportunities regarding the efficacy of naturally occurring compounds:

Efficacy revealed that L-carnitine-treated alternatives have all potential as observations that alter the dramatic clinical situation of patients suffering from lipid storage myopathy. The US Food and Drug Administration (FDA) not only allowed L-carnitine as a rare drug, but also included it on the list of lifesaving drugs.

In deeper insight into the pathological implications of major and secondary carnitine deficiency, there has been an impressive development of scientific and patent applications for L-carnitine, a substantially narrower range of acyl carnitine.

The use of L-carnitine has been described in the cardiovascular field for the treatment of cardiac arrhythmias and congestive heart failure (US Pat. No. 4,656,191), myocardial ischemia and oxygen deficiency (US Pat. No. 4,649,159); The field of fatty metabolism diseases for the treatment of hyperlipidaemia and lipoprotein hyperemia (US Pat. No. 4,315,944) and for the normalization of abnormal proportions of HDL to LDL + VLDL [US Pat. No. 4,255,449]; The entire parenteral nutrition field (US Pat. Nos. 4,254,147 and 4,320,145); The field of nephrology, which treats the onset of muscle spasms due to carnitine loss in dialysis fluids of ataxia and chronic uremic patients with regular hemodialysis (US Pat. No. 4,272,549); Neutralizing the toxic effects induced by anticancer agents such as adriamycin (US Pat. Nos. 4,400,371 and 4,713,379) and anesthetics including halogens such as halotane (US Pat. No. 4,780,308); Treatment of venous hemostasis [US Pat. No. 4,415,589]; Neutralizing many of the worsening parameters of biochemistry and behavioral science in outdated tasks [US Pat. No. 4,474,812]; It has been proposed for the normalization of triglyceride and tumor necrosis factor (TNF) levels in patients suffering from AIDS and asymptomatic HIV-serum-positive positives (US Pat. No. 5,631,288).

In addition, the use of L-carnitine has been suggested in compounds with other active ingredients, such as in the compound of coenzyme Q10, which has a wide range of L-carnitine and metabolism / antiatherogenic activity (US Pat. No. 4,599,232).

Regarding alkanoyl L-carnitine, the use of acetyl L-carnitine has been found in the treatment of central nervous system diseases, in particular Alzheimer's disease [US Pat. No. 4,346,107] and in the treatment of diabetic neuropathy [US Pat. No. 4,751,242]. While well known in the art, propionyl L-carnitine has been proposed for the treatment of peripheral vascular disease (US Pat. No. 4,343,816) and congestive heart failure (US Pat. No. 4,194,006).

The activity of the coenzyme nicodineamide adenine dinucleotide (NADH), whose role in energy steps is well known, is also complex.

The function of NADH in the respiratory chain is essential for the movement of electrons in the mitochondrial system and ATP formation.

Both NADH dehydrogenases are separated from the internal mitochondrial substrate. Perhaps the lower molecular weight (M.W. 78,000), NADH, is a larger complex (more than M.W. 300,000) subunits that are considered to be a functional form of naturally occurring systems.

Various complexes located on the inner mitochondrial membrane are chains of oxidative systems under the name of electrons, cytochromes, and coenzyme Q10 chains that allow the use of oxygen and ATP formation to be transferred from lower to higher potential systems. It is composed. In fact it comes from a respiratory chain that induces oxidative phosphorylation leading to the production of ATP from NADH.

Together with the cytochrome and coenzyme Q10 complexes, NADH is an element that requires the transformation of energy into ATP, and NADH, known at the beginning of this chain, is a major conditional element in this process.

Not only is the enzymatic function of NADH detected only in the energy-type reaction for ATP formation, but NADH is also a quinodihydroxy-pteridine reductase (DHPR), which recently progresses with the biosynthesis of H4-biopterin. It has been shown to act as a coenzyme necessary for.

The possibility of stimulating the biosynthesis of H4-biopterin and of increasing its concentration in the brain has recently been proposed as a method of increasing L-dopa. Therefore, dopamine shows deficiency in diseases such as Parkinson's disease, and this deficiency is considered neuropathy of the underlying Parkinson's syndrome. L-dopa, on the other hand, can act as a precursor of dopamine and metabolize itself, but not in the case of tyrosine, which can be considered as a precursor leading to the formation of L-dopa without the presence of tyrosine hydrolase. Do not.

In fact, reduction in this enzyme is known at the level of substantia nigra in Parkinson's syndrome patients. In addition, the reduction in tyrosine hydride is carried out by the strong reduction in the coenzyme, H4-biopterin, which is necessary for the synthesis of tyrosine hydride.

Since H4-biopterin does not cross the blood-brain barrier, direct dosing of H4-biopterin is unnecessary. However, on the contrary, it is H4-non-off by administration of the coenzyme necessary for the activation of quinodihydroxy-pteridine reductase (DHPR) for the formation of H4-biopterin, a function known to be performed by NADH. It helps to promote the formation of terrins and has been shown to be useful.

Therefore, administration of NADH actually activates DHPR, which leads to the formation of the H4-biopterin necessity to activate tyrosine hydrolase to achieve waveguide compatibility.

Clinical trials are based on intravenous administration of NADH to patients suffering from Parkinson's disease, whose validity of the theoretical assumption outlined above has been confirmed.

Patients treated in this way show significant improvement in Parkinson's disease symptoms.

A largely comparable result was obtained by oral administration of NADH using sustained release of the capsule in the stomach to avoid the acidic environment of the stomach leading to a rapid reduction in NADH levels to protect the doser.

In addition, clinical improvement of Alzheimer's disease and chronic fatigue syndrome (CFS) has been reported with NADH administration [Birkmayer J. G., Annals Clin. Lb. Sci., 26, 1 1996].

The present invention relates to a composition having activity in regulating central stage co-ordination to be effective in both metabolic and energy performance of skeletal muscle as well as muscle movement and both peripheral and central nervous system. Therefore, the present composition may be classified as a food supplement or a pure medicine according to whether the composition is used for a specific person, whether the purpose of use is auxiliary, prophylactic or totally therapeutic.

In particular, the compositions of the present invention as food supplements or prophylactic agents are particularly suitable for the promotion of skeletal muscle adaptation in persons with intense and prolonged physical activity and for overcoming the muscle fatigue and malaise seen in fragile persons without further or less intense physical activity.

Based on the properties of the compounds described above, the possibility of interaction between them is assessed by a series of tests performed on the composition of L-carnitine or an alkanoyl derivative thereof and NADH and / or NADPH. Surprising and unexpected synergistic interactions with the tests performed on these new compositions constituted compositions that were totally unpredictable based on our pharmacological knowledge of L-carnitine or its alkanoyl derivatives, NADH and NADPH. It was observed between the components.

The components of the present invention include the following components in the composition.

(a) L-carnitine or alkanoyl L-carnitine having a straight or branched alkanoyl group having 2 to 8 carbon atoms, preferably 2 to 6 carbon atoms, or a pharmacologically acceptable salt thereof;

(b) NADH or NADH precursors and / or NADPH;

(c) pharmacologically acceptable excipients;

Preferably the NADH precursor is nicotinamide.

The weight ratio of (a) :( b) is generally 1: 0.01 to 1: 1, preferably 1: 0.05 to 1: 0.5, for example 1: 0.1.

Alkanoyl L-carnitine is preferably selected from the group comprising acetyl L-carnitine, propionyl L-carnitine, butyryl L-carnitine, valeryl L-carnitine and isovaleryl L-carnitine.

For the purposes of the present invention what is meant by L-carnitine, acetyl L-carnitine, propionyl L-carnitine and isovaleryl L-carnitine is such a compound in the flameproof form.

What is meant by pharmacologically acceptable salts of L-carnitine or alkanoyl L-carnitine is any salt of these with acids that do not cause unwanted toxicity or side effects.

Non-limiting examples of such salts are chloride, bromide, iodide, aspartate, acid aspartate, citrate, acid citrate, tartrate, phosphate, acid phosphate, fumarate and acid fumarate, glycerophosphate, glucose Phosphates, lactates, maleates and acid maleates, orotates, oxalates, acid oxalates, sulfates, acid sulfates, trichloroacetates, trifluoroacetates, methane sulfonates.

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

The composition of the present invention further comprises vitamins, coenzymes, mineral substances, antioxidants.

In dosage units, the components of the present invention comprise, for example, (a) 100 to 500 mg of L-carnitine or alkanoyl L-carnitine or an equivalent of one of their pharmacologically acceptable salts and (b) NADH or NADPH. Weight ratio (a) :( b) from 1: 0.01 to 1: 1, preferably from 1: 0.02 to 1: 0.2.

For simplicity, reference is made only below to the composition of L-carnitine and NADH, but this is equally effective and effective for compositions of L-carnitine and NADPH or compositions of alkanoyl L-carnitine and NADH and / or NADPH. The present invention is applied to obtain the object of the present invention.

Toxicity test

Both carnitine and NADH have limited toxicity and good resistance. This excellent property was confirmed by intravenous administration of rats and mice with a composition of 100 mg / kg L-carnitine and 5 mg / kg NADH. In the sustained (30-day) toxicity study, oral administration of 250 mg / kg L-carnitine and 10 mg NADH did not reveal any mortality, toxicity or fragility because the animals were sufficiently resistant.

Blood-chemistry and histological observations were performed in several organs at the end of the treatment, which showed no abnormalities compared to the control group, and as a result confirmed the excellent resistance of the composition.

Muscle enzyme increase test after sustained exercise

Evaluation of the effects of carnitine and NADH as well as two compositions on the concentration of mitochondrial enzymes involved in muscle exercise, testing continued to increase muscle compared to controls responding to the greater energy demands required for sustained muscle effort. This was done to establish whether mitochondrial enzymes are active in the gastric muscle of rats under exercise.

To this end, the group of Wistar rats was placed in rats on a Rosaroid device (Basile, Como, Italy) at 20 m / min for 120 minutes daily (Benzi G., J. Appl Physiol., 38, 565, 1975). Muscle enzyme activity is assessed following isolation and homogenization of each rat muscle after 7 or 30 days of training (Oscai L. B., J. Biol. Med., 245, 6968, 1971). The enzymes that have been evaluated are citrate synthetases, isocitrate dehydrogenases and rotsinate dehydrogenases.

The results obtained in this test showed that the composition of carnitine and NADH could induce a very significant increase in enzyme activity only after 7 days of training. On the other hand, the observation time did not change, and enzyme activity was detected by comparing only one of carnitine or NADH with the control alone.

Strong synergistic effects of these two products were recorded after 30 days of training.

Increased test in rabbit papillary muscle ATP concentration after hypoxia

These tests have been used to evaluate whether or not the compound can be administered to hypoxic rabbits known to deplete energy compounds such as L-carnitine or NADH to maintain ATP levels in rabbit heart papillary muscle.

Tests were conducted daily for three days in New Zealand rabbits receiving intravenous infusion, either individually or together with L-carnitine (100 mg / kg) and NADH (10 mg / kg).

Another group of animals as a control group was not treated. Three days after all animal treatments were euthanized, their hearts were extracted and separated for papillary part diameter 1 mm, thickness 4.5 mm for measurement. The detached tissue was sprayed into a thermostatic bath, 100% saturated O ₂ solution. Experimental hypoxia was filled with 100% N ₂ in the bath instead of O ₂ . The ATP content of papillary muscle was analyzed using the method described by Strehler BL [Strehler BL, Methods in Enzymology III. New York. Acad. Press, 871, 1957]. The analysis was performed on tissue specimens that maintained normal perfusion for 90 minutes, and also on tissue specimens after sustained 90 minute hypoxia.

This test showed that ATP concentrations were substantially reduced in both control animals and animals treated with either only carnitine or only NADH alone. On the other hand, complete protection against ATP reduction due to hypoxia has been found in animals treated with carnitine and NADH compositions.

Therefore, this test cannot be obtained using either L-carnitine alone or NADH alone, and L-carnitine to protect ATP present in the papillary muscle against reduction by hypoxia in the range that can be reduced using the composition. And the ability of the composition of NADH.

Test for the ability of L-carnitine and NADH to promote dopamine production

This test was performed in a range of 15 million to 30 million to 60 million cell concentrations in which both components were cultured in 200 μg NADH / ml or 2 mg / mL of L-carnitine or in composition in neuroblastoma cell culture.

The production of dopamine induced by NADH and L-carnitine is described by Johnson and Keller [Jonsson G., Holman H., Adams R. N., Central adrenaline neurones. Ed. De Fuxe-Pergamon Press, 59, 1980; Keller R., Oke A., Mefford I., Life Sciences, 19, 995, 1976] were analyzed by HPLC according to the modified Meyer method [Mayer G. S., Strong R. F., Current separation 4, 44, 1982]. The results of these tests demonstrate that the addition of NADH to cell culture effectively leads to increased dopamine production associated with cell number.

However, L-carnitine, which alone shows a very small effect, can be obtained with significant increase when added to NADH solution.

Therefore, synergistic effects were also recorded in this test.

[Increase percentage of dopamine synthesis in neuroblastoma cell cultures cultured with NADH or carnitine as a function of cultured cell number (millions)]

MPTP (1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine) test

The use of MPTP as a neurotoxin primarily at the level of the neuroskeletal muscle system will be an important experimental model for the study of Parkinsonism and its biochemical and clinical etiology.

High doses of MPTP (40 mg / kg) in both monkeys and rats induce hypokinetic and bradykinetic symptoms, typical of Parkinson's disease, carried out by significant reduction of dopase and its metabolites. do.

In this trial, whether behavioral and motility disorders were induced by MPTP in rats, as well as dopamine concentrations that could be corrected and corrected by administration of NADH or L-carnitine or the composition, were corrected.

A 20 g C57 BE / 6 black rat was used for this test. One group of these mice was used as a control and the other group was injected subcutaneously with 40 mg / kg MPTP at 24 hour intervals. After 3 weeks of infusion of MPTP the motility of all treated and control animals was assessed. Waveguide analysis was also performed 3 weeks after MPTP treatment. Treatment with both NADH and carnitine is given immediately prior to the start of the exercise test. Mobility is assessed using a plexiglas camera penetrated at different heights by two infrared rays according to the procedure described by Archer (Archer T., Fredrikson A., Psychopharmacology, 88, 141, 1986).

The decrease in motility induced by MPTP was found to be greater than 80% in control rats, and relative to that of NADH and L-carnitine alone, motility was reduced by 60% and 70%, whereas the motility of the composition of the two substances was substantially This will restore the normal level (20% reduction). In addition, the results for the waveguide concentration in the rhabdomyomus, which showed almost normal levels in the treated mice, was reduced by 90% in the control mice.

In this test, too, the effect of L-carnitine alone was negligible, while NADH had an equivalent effect of up to 40%, and the composition restored waveguide to a level very close to the concentration normally seen in this tissue.

Examples of compositions according to the invention are shown below:

(1) L-carnitine molecule flame resistance mg 200

NADH mg 5

(2) L-carnitine molecule flame resistance mg 200

NADH mg 10

(3) Acetyl L-Carnitine Molecular Inflammation mg 250

NADH mg 5

(4) Acetyl L-Carnitine Molecular Flameproof mg 500

NADH mg 10

(5) Propionyl L-Carnitine Molecular Inflammation mg 250

NADH mg 5

(6) L-carnitine molecule flame resistance mg 200

NADH mg 5

Coenzyme Q10 mg 20

Pyridoxine mg 3

Selenium mg 20

Zinc mg 2

(7) L-carnitine molecule flame resistance mg 200

NADH mg 5

Coenzyme Q10 mg 20

Taurine mg 10

Inosine mg 100

Creatine mg 100

Pyruvic acid mg 10

The present invention relates to a food supplement and chronic fatigue syndrome for an individual or a weak person engaged in intense physical activity with a composition containing L-carnitine or alkanoyl L-carnitine or a pharmacologically acceptable salt thereof and NADH and / or NADPH. It is useful as a medicament for the treatment of Parkinson's disease.

Claims (12)

(a) L-carnitine or alkanoyl L-carnitine having a straight or branched alkanoyl group having 2 to 8 carbon atoms, preferably 2 to 6 carbon atoms, or a pharmacologically acceptable salt thereof; (b) a reduced form of nicotinamide adenine dinucleotide (NADH) or a precursor thereof, and / or a reduced form of nicotinamide adenine dinucleotide phosphate (NADPH); And (c) a pharmacologically acceptable excipient The composition characterized in that it is included. The composition of claim 1, wherein said NADH precursor is nicotinamide. The composition according to claim 1 or 2, wherein the weight ratio of (a) :( b) is from 1: 0.01 to 1: 1. The composition according to claim 3, wherein the weight ratio of (a) :( b) is 1: 0.02 to 1: 0.2. The composition of claim 4, wherein the weight ratio of (a) :( b) is 1: 0.1. The method of claim 1, wherein the alkanoyl L-carnitine is selected from acetyl L-carnitine, propionyl L-carnitine, butyryl L-carnitine, valeryl L-carnitine and isovaleryl L-carnitine. Composition. The method of claim 1, wherein the pharmacologically acceptable salt is selected from the group consisting of chloride; Bromide; Iodide; Aspartate, acid aspartate; Citrate, acid citrate; Tartrate; Phosphates, acid phosphates; Fumarate, acid fumarate; Glycerophosphate; Glucose phosphate; Lactates; Maleate; Acid maleate; Orotate; Oxalate; Acid oxalate; Sulfates, acid sulfates; Trichloroacetate; Composition selected from trifluoroacetate and methane sulfonate. 8. The composition of any one of claims 1 to 7, wherein the composition further contains vitamins, coenzymes, mineral substances and antioxidants. The composition according to claim 1 or 2, wherein the composition comprises (a) 100 to 500 mg of L-carnitine or alkanoyl L-carnitine or a pharmacologically acceptable salt thereof and (b) a NADH, NADH precursor or A composition containing NADPH effective content, wherein the weight ratio of (a) :( b) is from 1: 0.01 to 1: 1. The composition of claim 4, wherein the composition comprises (a) 100 to 500 mg of L-carnitine or alkanoyl L-carnitine or a pharmacologically acceptable salt thereof, and (b) an NADH, NADH precursor or NADPH effective amount. And a weight ratio of (a) :( b) is 1: 0.02 to 1: 0.2. The composition of any one of claims 1 to 10, wherein the composition is administered orally and in the form of food supplements. The composition of claim 1, wherein the composition is administered in oral or parenteral form.