CN1299283A - Composition comprising L-carnitine or an alkanoyl L-carnitine and NADH and/or NADPH - Google Patents

Abstract

A composition is disclosed which comprises L-carnitine or an alkanoyl L-carnitine or the pharmacologically acceptable salt thereof and NADH and/or NADPH, useful as a dietary supplement for individuals engaging in strenuous physical exercise or asthenic subjects and, as a medicament, for treating the chronic fatigue syndrome and Parkinson's disease.

Description

Compositions comprising L-carnitine or alkanoyl L-carnitine and NADH and/or NADPH

The present invention relates to a composition that acts both on the metabolic and energy performance of skeletal muscle and on the regulation of muscle movement and coordination at the central level by strengthening the peripheral muscles and at the level of the central nervous system. Thus, the composition can take the form and function of a food additive or a true medicine, depending on its supportive or prophylactic effect, or a strictly therapeutic effect, the composition acting on the particular individual to whom it is administered.

Specifically, as a food additive or prophylactic, the composition according to the invention is particularly suitable for promoting the adaptation of the skeletal muscles of individuals engaged in prolonged intense physical activity, and also for combating the feeling of muscle fatigue and exhaustion in frail persons, even if He did not engage in more or less vigorous physical activity of any kind at all.

Whether professional or amateur, people who engage in sports hope to achieve the maximum adaptation of skeletal muscles in a short period of time, and then maintain it for as long as possible, so as to be able to continue strong physical activity for a long time. The need for this optimal state of fitness can lead to inappropriate use of drugs, especially steroids. Drugs of this class are known to increase protein synthesis, thereby enhancing muscle mass growth to a degree far beyond that achieved by training and diet. However, the use of these drugs is illegal and undoubtedly harmful to professional sports.

Obviously, the only legitimate way to achieve the above-mentioned purpose is to carry out an appropriate training program, combined with an appropriate diet, which is fortified by the addition of appropriate food additives.

The term "frailty" here means a widespread non-specific symptom characterized by a burden of life, currently prevalent in major metropolitan and prosperous areas, involving large populations, mostly independent of factors such as age and social status, characterized by Lack or loss of muscle strength, easy fatigue, and inadequate response to stimuli.

When used as a serious therapeutic agent, a particular application of the compositions of the present invention is in the treatment of chronic fatigue syndrome and Parkinson's disease, as well as idiopathic Parkinson's-like symptoms caused by the administration of illicit drugs.

First formally described in the Annals of Internal Medicine 1988, Chronic Fatigue Syndrome (CFS) is a disorder characterized by an unexplained degree of fatigue, often far greater in intensity than in very serious diseases such as tumors and AIDS. Fatigue, a debilitating degree resulting in a reduction of more than 50% in work activities and normal social relationships for more than 6 months.

According to the diagnostic criteria for CFS described in Annals of Internal Medicine (December 1994), patients must have at least four of the following eight symptoms for more than 6 months:

1. Neuropsychological disorders such as memory loss, hyperexcitability, confusion, difficulty thinking and concentrating;

2. Pharyngitis;

3. Tender cervical or axillary lymph nodes;

4. Muscle pain;

5. Migratory arthralgia, but without any joint swelling;

6. Diffuse headache, which is different in type, character and severity from the patient's previous headache;

7. Sleep disorders, characterized by insomnia or hypersomnia or drowsiness;

8. Pervasive fatigue and malaise lasting 24 hours or more after physical activity that was previously easily tolerable.

Parkinson's disease is generally considered an idiopathic condition, whereby it is well known that Parkinsonian symptoms can be caused by drugs of abuse such as phenothiazines, butyrophenones and reserpine. Recently, parkinsonism in drug abusers who self-injected compounds similar to meperidine, the abused synthesis of which gives MPTP and MPPP, was studied.

In fact, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP or NMPTP) and 1-methyl-4-phenyl-propoxy-piperidine (MPPP) select Sexual destruction of dopaminergic neurons in the substantia nigra induces clinically, pathologically, biochemically and pharmacologically similar symptoms to spontaneous Parkinson's disease both for humans and primates other than humans.

The similarity between idiopathic parkinsonism and MPTP-induced parkinsonism is so great that it has been postulated (Burns et al.: 1-methyl-4-phenyl-1,2,3,6- Neurotoxicity of tetrahydropyridine in monkeys and humans (Canadian Journal of Neuroscience, 11, n.1 (suppl.), 166-168, February 1984), this induced parkinsonism "may be constructed not only Only one model. MPTP-induced parkinsonism suggests a putative toxic etiology for Parkinson's disease."

The therapy of choice for the management of Parkinson's disease is currently based on the administration of levodopa (L-dopa), a metabolic precursor of dopamine that does not itself cross the blood-brain barrier.

Since levodopa is metabolized sufficiently before it can reach its site of action in the brain, it should be administered in very high doses. L-dopa is then administered in combination with carbidopa, a dopa decarboxylase inhibitor that prevents systemic metabolism of levodopa before it reaches the brain.

Side effects such as anorexia, nausea, vomiting, and orthostatic hypotension may occur when levodopa is administered alone, although these symptoms largely resolve once carbidopa is also administered.

However, unpleasant side effects may frequently occur after several months of treatment with L-dopa, even in combination with decarboxylation inhibitors: dyskinesias of the face, trunk and extremities. In most cases, the occurrence of dyskinesias indicates that the dose of the drug has reached a critical threshold that must not be exceeded.

Therefore, there is an urgent need for a supportive/preventive/therapeutic agent, as a result of its efficacy, substantially non-toxic and side-effect-free, both in the simple need of appropriate food additives and also in the case of the initial occurrence of symptoms of the above-mentioned pathological states, can be safely used by a wide range of users.

These multiple objectives - to provide a supportive, prophylactic and strict therapeutic agent - have been achieved by the composition of the present invention, as described in detail below, in a novel combination comprising L-botulinum toxin Alkaline or lower C2-C6 alkanoyl L-carnitine or its pharmaceutically acceptable salt as the basic component, also contains nicotinamide adenine dinucleotide (NADH) or NADH precursor and/or nicotinamide adenine dinucleotide The reduced form of nucleotide phosphate (NADPH).

In the past few decades, a fundamental discovery (Fritz.I.B.: Metabolic Consequences of the Effect of Carnitine on the Oxidation of Long-Chain Fatty Acids, edited by F.C. Gran, New York, Academic Press, 1968, pp.39- 63) Yes, L-carnitine is unique in its important physiological role as a carrier of long-chain fatty acids across the mitochondrial membrane and into the mitochondrial matrix, where they are oxidized, as a result of this discovery, as well as First thought (Engel and Angelini Science 1973, 179:899-902) that primary L-carnitine deficiency was the cause of a severe form of myopathy (lipid storage myopathy), which, although rare, is sometimes fatal Thus, to the best of our knowledge, significant progress has been made on the pathological consequences of primary and secondary L-carnitine deficiency, whereas the therapeutic and nutritional value of exogenously supplemented L-carnitine has no progress.

Carnitine exists in all biological tissues in high concentrations of free carnitine and in low concentrations of acylcarnitines, which are metabolites of the following reversible reactions: acyl CoA + carnitine, acylcarnitine + CoASH

The reaction is catalyzed by three groups of enzymes, the transferases, which are mainly distinguished by their specificity for the substrates of the enzyme reagents: carnitine acetyltransferases (CAT), whose substrates are short-chain acyl groups such as acetyl and propionyl ); carnitine octanoyltransferase (COT), whose substrate comprises medium-chain acyl groups; and carnitine palmitoyltransferase (CPT), whose substrate comprises long-chain acyl groups.

The important role of carnitine in intermediary metabolism, especially with regard to its limited biosynthesis, may explain how carnitine deficiency occurs as a secondary event in various pathological functions involving different organs and systems. The expanded clinical scope reflects increased therapeutic opportunities related to the efficacy of this natural compound; when it was observed that L-carnitine replacement therapy dramatically reversed the clinical manifestations of patients with lipid storage myopathy, the significance of this efficacy was revealed Overall scope and magnitude. The U.S. Food and Drug Administration (FDA) has not only granted L-carnitine an "orphan drug" status, but has also included it in its list of "life-saving" drugs.

As far as we know, there have been numerous scientific papers and patent publications on the pathological implications of primary and secondary carnitine deficiency, mostly targeting L-carnitine and rarely some acyl carnitine.

According to our incomplete investigation of the patent situation, it has been proposed to use L-carnitine in the cardiovascular field for the treatment of arrhythmia and congestive heart failure (US4656191), myocardial ischemia and myocardial hypoxia (US 4649159); Used in the field of lipid metabolism disorders, for the treatment of hyperlipidemia and hyperlipoproteinemia (US 4315944), for correcting abnormal HDL:LDL-VLDL ratios (US 4255449); in the field of overall parenteral nutrition (US4254147 and US 4320145); in nephrology for use against chronic uremic patients undergoing regular hemodialysis therapy for muscle weakness and myalgic cramps caused by loss of carnitine in the dialysate (US 4272549); for use against Toxic effects induced by anticancer agents such as doxorubicin (US 4400371 and US 4713370) and by halogenated anesthetics such as halothane (US 4780308); for the treatment of venous stagnation (US 4415589); for use against the elderly Decline in a number of biochemical and behavioral indicators (US 4474812); for correction of triglyceride and tumor necrosis factor (TNF-α) levels in AIDS patients and asymptomatic HIV-positive patients (US5631288).

It has also been proposed to use L-carnitine in combination with other active ingredients, such as L-carnitine coenzyme Q10 (US4599232), which has broad-spectrum metabolic/anti-atherosclerotic effects.

As for alkanoyl L-carnitine, acetyl L-carnitine is known for the treatment of central nervous system disorders, especially Alzheimer's disease (US 4346107), for the treatment of diabetic neuropathy (US 4751242), And propionyl L-carnitine has been used to treat peripheral vascular disease (US4343816) and congestive heart failure (US4194006).

Equally complex is the activity exerted by the coenzyme nicotinamide adenine dinucleotide (NADH), whose effects on the energy level are well known.

Its function in the respiratory chain is essential for electron transport in the mitochondrial system and ATP formation. Two NADH dehydrogenases have been isolated from the inner mitochondrial matrix. The small molecular weight ones (M.W. 78000) are likely subunits of larger complexes (M.W. over 300000), which are considered to be the naturally derived functional forms of this system.

Various complexes located in the inner mitochondrial membrane make up a series of oxidative systems, named cytochrome and coenzyme Q10 chains, which utilize oxygen and the formation of ATP to allow the transfer of electrons from a low-potential system to a high-potential system. In fact, oxidative phosphorylation comes from the respiratory chain, leading to the production of ATP from NADH.

NADH, along with the cytochrome and coenzyme Q10 complex, is essential for the conversion of energy to ATP, and NADH, found at the beginning of the chain, is the main regulator of this process.

Not only is the enzymatic function of NADH detectable in the energy-type reactions that form ATP, but it has recently been shown that NADH acts as a coenzyme for the biosynthesis of H4-biopterin to quinine dihydroxy-pteridine reductase (DHPR) is necessary.

The possibility of stimulating the biosynthesis of H4-biopterin and increasing its concentration in the brain has recently been proposed as a pathway to increase L-dopa and thus dopamine, which are deficient in diseases such as Parkinson's syndrome, This deficiency is thought to underlie Parkinson's disease neuropathy. Although L-dopa can act as a precursor of dopamine, which can be converted to the latter through metabolism, in the absence of tyrosine hydroxylase, this conversion does not occur to tyrosine, although it can also be considered as a A precursor capable of causing the formation of L-dopa. This enzyme has in fact been found to be reduced at the level of the substantia nigra in Parkinson's disease patients. Moreover, the reduction in hydroxytyrosine was accompanied by a marked reduction in H4-biopterin, a coenzyme necessary for the synthesis of hydroxytyrosine. Since H4-biopterin does not cross the blood-brain barrier, direct administration of H4-biopterin is not useful, in contrast, resorting to stimulation of H4-biopterin formation seems to be useful and also That is, the administration of a coenzyme necessary for the activity of quinine dihydroxy-pteridine reductase (DHPR) to form H4-biopterin, a function known to be performed by NADH. Thus, NADH administration activates DHPR, leading to the formation of H4-biopterin, which in turn is necessary for the activation of tyrosine hydroxylase, thereby enabling the de novo synthesis of dopa.

Clinical trials based on the intravenous administration of NADH to patients with Parkinson's disease have confirmed the validity of the above theoretical assumptions, and the symptoms of Parkinson's disease in the treated patients were significantly improved.

Oral administration of NADH has achieved roughly equivalent results, and attention should be paid to the use of delayed-release gastrointestinal capsules for administration to avoid a rapid decrease in NADH levels caused by the acidic environment of the stomach.

Clinical improvement in Alzheimer's disease and Chronic Fatigue Syndrome (CFS) has also been reported with NADH administration (Birkmayer J.G., Annals of Clinical Laboratory Science 26, 11996).

Based on the characteristics of the aforementioned compounds, the possibility of their interaction was assessed by means of a series of tests carried out on the combination of L-carnitine or its alkanoyl derivatives with NADH and/or NADPH. With the help of experiments carried out on these novel combinations, a surprising and unexpected synergistic interaction between the components of the combination was observed, which was demonstrated in our study of L-carnitine or its alkanoyl derivatives and NADH And the pharmacological knowledge base of NADPH is totally unpredictable.

The composition of the present invention comprises the following components in combination with each other:

(a) L-carnitine or an alkanoyl L-carnitine, wherein the linear or branched alkanoyl group has 2-8, preferably 2-6 carbon atoms, or their pharmaceutically acceptable one of the salt

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

(c) Pharmaceutically acceptable excipients.

Preferably, the NADH precursor is nicotinamide.

The weight ratio of (a) to (b) is generally from 1:0.01 to 1:1, should preferably be from 1:0.05 to 1:0.5; for example, the weight ratio may be 1:0.1.

Alkanoyl L-carnitine should preferably be selected from the group consisting of acetyl L-carnitine, propionyl L-carnitine, butyryl L-carnitine, valeryl L-carnitine and isovaleryl L-carnitine Group of bases. Acetyl L-carnitine and propionyl L-carnitine are particularly preferred.

For the purposes of the present invention, L-carnitine, acetyl L-carnitine, propionyl L-carnitine and isovaleryl L-carnitine mean the internal salt forms of these compounds.

The pharmaceutically acceptable salts of L-carnitine or alkanoyl L-carnitine mean any salts of these compounds with acids that do not cause unwanted toxicity or side effects. These acids are well known to pharmacologists and pharmaceutical experts.

Non-limiting examples of salts are: chloride; bromide; iodide; aspartate, acid aspartate; citrate, acid citrate; tartrate; Salt; Fumarate, Acid Fumarate; Glycerophosphate; Glucophosphate; Lactate; Maleate, Acid Maleate; Orotate; Oxalate, Acid Oxalate; Sulfate, Acid Sulfate; Trichloroacetate; Trifluoroacetate and Methanesulfonate.

A list of FDA-approved pharmaceutically acceptable salts can be found in International Journal of Pharmacy 33, (1986), 201-217, incorporated herein by reference.

The composition of the present invention may further contain vitamins, coenzymes, minerals and antioxidants.

In unit dosage form, the composition of the present invention comprises, for example, 100-500 mg of (a) L-carnitine or an alkanoyl L-carnitine, or an equivalent amount of one of their pharmaceutically acceptable salts, and a certain (b) NADH or NADPH by weight such that the weight ratio of (a) to (b) is from 1:0.01 to 1:1, preferably from 1:0.02 to 1:0.2.

For the sake of brevity, the following will only refer to the combination of L-carnitine and NADH, although it is self-evident that the combination of L-carnitine and NADPH or the above-mentioned alkanoyl L-carnitine with NADH and/or NADPH are equally effective, so as to fully achieve the purpose of the present invention.

Toxicology test

Both carnitine and NADH are known to have only limited toxicity and are well tolerated. Intravenous administration of up to 100 mg/kg L-carnitine in combination with 5 mg/kg NADH to rats and mice confirmed these desirable characteristics. In a long-term (30 day) toxicity study, oral administration of 250 mg/kg L-carnitine in combination with 10 mg NADH was well tolerated by the treated animals, producing neither lethality nor toxicity nor intolerance Sexual signs. Blood chemical and histological examination of the various organs performed after the end of treatment revealed no abnormalities compared to control animals, thus confirming that the studied combination was well tolerated.

Muscle Enzyme Increase Test After Prolonged Exercise

In order to assess the effect of carnitine and NADH and the combination of both on the concentration of mitochondrial enzymes involved in muscle activity, experiments were performed to determine whether the activity of these mitochondrial enzymes could be increased in the gastrocnemius muscle of rats subjected to prolonged muscle activity compared to control animals, To meet the greater energy demands of prolonged muscular effort. Muscle training was performed on a group of Wistar rats by placing them on a Rotaroid apparatus (Basile, Como, Italy) at a speed of 20 m/min for 120 minutes per day (Benzi G., Journal of Applied Physiology 38, 565, 1975). The gastrocnemius muscle of each rat was isolated and homogenized after seven or thirty days of training, and the activities of muscle enzymes were assessed (Oscai L.B., Biomedical Journal 245, 6968, 1971). The enzymes evaluated were citrate synthase, isocitrate dehydrogenase and succinate dehydrogenase.

The results obtained in this trial demonstrated that the combination of carnitine and NADH was able to induce a significant increase in enzyme activity after only seven days of training, whereas no changes were detectable with either carnitine or NADH alone compared to controls at this observation time.

The strong synergy of the two products was even more evident after thirty days of training. Treatment training days, citrate synthetase, alien -citric acid dehydrogenase, amber -dehydrogenase, 0 20.9 ± 1.4 2.25 ± 0.31 3.79 ± 0.22 control 7 22.1 ± 1.6 2.30 ± 0.20 3.90 ± 0.19 Comparison 30 29.9 ± 2.1 3.33 ± 5.20 ± ± 0.30肉毒碱250mg/kg    0       20.8±0.95     3.05±0.19      3.35±0.35肉毒碱250mg/kg    7       22.6±1.9      2.85±0.31      3.85±0.45肉毒碱250mg/kg    30      30.1±0.95     2.98±0.16      4.90±0.33NADH 10mg/kg     0       21.5±1.4      2.35±0.29      3.60±0.21NADH 10mg/kg     7       30.5±2.5      3.65±0.55      4.15±0.45NADH 10mg/kg     30      33.6±2.1      3.55±0.36      5.40±0.45肉毒碱250mg/kg    0       21.4± 1.9 2.15 ± 0.18 3.80 ± 0.22+NADH 10mg/Kg Botox 250mg/Kg 77.7 ± 3.92 5.1 ± 0.29 7.15 ± 0.30+NADH 10mg/kg Botox 30 75.9 ± 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 9.25.5 9.3 ± NADH 10mg/kg

(*) Enzyme activity is expressed in μmol of substrate used per min/g tissue weight

Increase of ATP Concentration in Rabbit Papillary Muscle After Hypoxia

These assays were used to assess whether L-carnitine and NADH, or a combination of the two, was able to maintain ATP concentrations in the papillary muscle of the rabbit heart after hypoxia, which is known to cause depletion of this energy compound. Tests were carried out on New Zealand rabbits and the animals received daily intravenous injections of L-carnitine (100 mg/kg) and NADH (10 mg/kg) alone, as well as a combination of the two substances, for three consecutive days.

Another group of animals served as a control group and received no treatment. After the third day of treatment, all the animals were sacrificed, the heart was taken out, and papillary muscle slices with a diameter of 1 mm and a thickness of 4.5 mm were separated. The isolated tissues were perfused in a thermostat filled with 100% saturated _O2 solution. Then add 100% _N2 instead of _O2 to the constant temperature bath to cause experimental hypoxia. The ATP content of the papillary muscle was analyzed by the method described by Strehler BL (Strehler BL "Methods in Enzymology III", New York. Acad. Press, 871, 1957). Tissue samples were analyzed both after 90 minutes of normal perfusion and after 90 minutes of continuous hypoxia.

These experiments showed that ATP concentrations were substantially reduced in both control animals and animals treated with carnitine alone or NADH alone. On the other hand, in animals treated with the combination of carnitine and NADH, a complete protection against the reduction of ATP induced by hypoxia was found.

These experiments were thus able to reveal the ability of the combination of L-carnitine and NADH to protect the ATP present in the papillary muscles against the reduction induced by hypoxia to a degree not achieved by either L-carnitine or NADH alone Yes, amazingly, this combination can be achieved. ATP concentration (mol/g tissue)

Treatment Before Hypoxia After Hypoxia

Control 1.54±0.31 0.40±0.051

Carnitine 100mg/kg 1.65±0.28 0.55±0.031

NADH 10mg/kg 1.60±0.30 0.65±0.044 Carnitine 100mg/kg+NADH 10mg/kg 1.90±0.37 1.52±0.061

The test of the ability of L-carnitine and NADH to stimulate the production of dopamine

These experiments were performed on neuroblastoma cell cultures grown with 200 μg NADH/ml or 2 mg/ml L-carnitine or a combination of these two components at cell concentrations ranging from 15-30 to 60 million cells.

Dopamine production induced by NADH and L-carnitine was determined by HPLC according to the method of Mayer (Mayer G.S., Strong R.F., Currentseparation 4, 44, 1982), which was modified by Jonsson and Keller (Jonsson G., Holman H. , Adams R.N., "Central Adrenergic Neurons" Ed. De Fuxe-Pergamon Press, 59, 1980; Keller R., Oke A., Mefford I., "Life Science" 19,995, 1976). These experimental results demonstrate that the addition of NADH to cell cultures effectively increases dopamine production, which correlates with the number of cells.

A significant increase was obtained when L-carnitine was added to the NADH solution, whereas L-carnitine alone produced only a slight effect. Therefore, synergy is also evident in these experiments.

Percent increase in dopamine synthesis in cultures of neuroblastoma cells (N.cells) incubated with NADH or carnitine as a function of number of cells cultured (millions) Treatment % increase in N.cells % increase in N.cells N.cells increase %

(Million) (Million) (Million) (Million) Nadh 100 μg/ML 15 4.5 30 31.5 60 45.5NADH 200 μg/ml 15.8 3 40.6 60 55.6 Botoxine 1mg/ML 15-30 2.1 60 5.6 Botoxine. 2mg/ml 15-30 3.3 60 6.6nadh 100 μg/ml+15 6.6 30 45.2 60 50.6 Botox 1mg/mlnadh 200 μg/ml+15 18.4 56.4 60 70.5 Botaxer 2mg/ml

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

The use of MPTP as a neurotoxin active primarily at the level of the neuroskeletal system may be a remarkable experimental model for the study of Parkinson's syndrome and its biochemical and clinical pathogenesis.

In monkeys and mice, high doses of MPTP (40 mg/kg) induced symptoms of hypokinesia and bradykinesia, which are hallmarks of Parkinson's disease, accompanied by marked reductions in dopa and its metabolites. In these experiments, it was investigated whether MPTP-induced behavioral and motor impairments and dopamine concentrations in mice could be altered and corrected by administration of NADH or L-carnitine alone or in combination.

These experiments used C57 BE/6 black mice with a body weight of 20 g; one group of mice served as a control, and the other group received two subcutaneous injections of 40 mg/kg MPTP with an interval of 24 hours. Three weeks after MPTP injection, all treated and control animals were evaluated for motility. Dopa was also measured three weeks after MPTP treatment. Motility testing begins immediately after treatment with both NADH and carnitine; proceed as described by Archer (Archer T., Fredrikson A., Psychopharmacology 88, 141, 1986), using organic A glass camera assesses motility with two types of infrared light.

The reduction in motility induced by MPTP was demonstrated in control mice by more than 80%, NADH and L-carnitine alone reduced motility by 60% and 70%, respectively, while the combination of these two substances almost restored motility to normal levels (20% reduction). Also of interest were the results of dopa concentrations in striatal muscles, which were reduced by 90% in MPTP-administered control mice, but nearly normal levels in treated mice. Also, in these trials the effect of L-carnitine alone appears to be almost negligible, the effect of NADH alone is equal to 40%, whereas the combination restores dopa to levels very close to normal tissue concentrations .

Some composition examples according to the present invention are reported below: (1) L-endoxine inner salt mg 200

NADH mg 5(2) L-carnitine inner salt mg 200

NADH mg 10(3) Acetyl L-carnitine inner salt mg 250

NADH mg 5(4) Acetyl L-carnitine inner salt mg 500

NADH mg 10(5) propionyl L-carnitine inner salt mg 250

NADH mg 5(6) L-carnitine inner salt mg 200

NADH mg 5

Coenzyme Q10 mg 20

Pyridoxine mg 3

Selenium mg 20

Zinc mg mg 2(7) L-carnitine inner salt mg 200

NADH mg 5

Coenzyme Q10 mg 20

Taurine mg 10

Inosine mg 100

Creatine mg 100

Pyruvic acid mg 10

Claims (12)

1, compositions comprises:

(a) L-carnitine or alkanoyl L-carnitine, wherein this alkanoyl is a straight or branched, have 2-8, be preferably 2-6 carbon atom, or their pharmaceutically acceptable salts;

(b) reduction form (NADH) or its precursor of nicotinamide adenine dinucleotide, and/or the reduction form (NADPH) of nicotinamide-adenine dinucleotide phosphate salt; With

(c) pharmaceutically acceptable excipient.

2, the compositions of claim 1, wherein this NADH precursor is a nicotiamide.

3, claim 1 or 2 compositions, wherein (a): weight ratio (b) was from 1: 0.01 to 1: 1.

4, the compositions of claim 3, wherein (a): weight ratio (b) was from 1: 0.02 to 1: 0.2.

5, the compositions of claim 4, wherein (a): weight ratio (b) is 1: 0.1.

6, the compositions of claim 1-5, wherein this alkanoyl L-carnitine is selected from the group of being made up of acetyl L-carnitine, propionyl L-carnitine, butyryl L-carnitine, valeryl L-carnitine and isovaleryl L-carnitine.

7, the compositions of any aforementioned claim, wherein pharmaceutically acceptable salt is selected from by chloride; Bromide; Iodide; Aspartate, the acid aspartate; Citrate, the acid citrate; Tartrate; Phosphate, acid phosphate; Fumarate, acid fumarate; Glycerophosphate; Glucose phosphate salt; Lactate; Maleate, acid maleate; Orotate; Oxalates, acid oxalate; Sulfate, bisulfate; Trichloroacetate; The group that trifluoroacetate and mesylate are formed.

8, the compositions of any aforementioned claim further comprises vitamin, coenzyme, mineral and antioxidant.

9, claim 1 or 2 compositions; (a) the L-carnitine or the alkanoyl L-carnitine that in unit dosage forms, comprise 100-500mg; or its pharmaceutically acceptable salt of equivalent; with a certain amount of (b) NADH, NADH precursor or NADPH, make (a) and weight ratio (b) from 1: 0.01 to 1: 1.

10, the compositions of claim 4; (a) the L-carnitine or the alkanoyl L-carnitine that in unit dosage forms, comprise 100-500mg; or its pharmaceutically acceptable salt of equivalent; with a certain amount of (b) NADH, NADH precursor or NADPH, make (a) and weight ratio (b) from 1: 0.02 to 1: 0.2.

11, the compositions of any aforementioned claim is the form of food additive that can be oral.

12, the compositions of any aforementioned claim is can be oral or the medicament forms of parenteral.