CZ20003831A3 - Preparation containing L-carnitine or L-carnitine alkanoyl and NADH and/or NADPH - Google Patents

Abstract

A composition comprising L-carnitine or alkanoyl-Lcarnitine is disclosed or a pharmacologically acceptable salt thereof and NADH and / or NADPH suitable as an additional diet for an individual having exhaustive physical strain or for asthenic individuals and medicines to treat chronic exercise syndrome and Parkinson's disease

Description

Preparation containing L-carnitine or alkanoyl L-carnitine and NADH and / or NADPH

Technical field

The present invention relates to a composition which acts on both metabolism and skeletal muscle energy performance and muscle coordination and coordination at the central level by potentiating the effects of both the peripheral muscle and the central nervous system. The preparation may be formulated in a suitable form and act as a dietary supplement or as a real medicament, depending on whether it is a supportive or preventive or a strictly therapeutic effect on the individual for whom the preparation is intended and on which it is intended to act.

BACKGROUND OF THE INVENTION

As a dietary supplement or preventative preparation, the composition of the invention may be particularly useful both to facilitate the adaptation of the skeletal muscle of an individual engaged in prolonged physical activity and to the perception of muscular fatigue and fatigue known to asthenic individuals without any form of more or less intense physical exercise.

Anyone who is engaged in sports activities, whether professional or amateur, wishes to achieve in a short period of time and then maintain as long as possible skeletal muscles adapted to intense physical activity as long as possible. Searching for this optimal state of fitness may lead to inappropriate drug use, especially steroids. It is well known that these preparations can improve protein synthesis and consequently enhance muscle growth more than would be achieved by exercise or diet. The use of these products is both illegal and indisputably harmful when done in professional sports.

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The only way to achieve this is to properly exercise the appropriate training programs in combination with a suitable diet enhanced by the addition of appropriate dietary supplements.

By "asthenia" is meant an overlapping set of non-specific symptoms, typical of stressful living conditions commonly found in most urban agglomerations and built-up areas, and refers to a broad population regardless of factors such as age and social background, and this asthenia is characterized by loss of muscle strength with easy fatigue and inadequate responses to stimuli.

When used strictly as a therapeutic agent, one particular application of the formulation of the invention is the treatment of chronic fatigue and Parkinson's disease syndrome and spontaneous parkinsonism-like syndrome caused by the administration of unauthorized preparations.

Chronic Fatigue Syndrome (CFS) officially first described in 1988 by the Annals of International Medicine is a disease characterized by a degree of fatigue that is inexplicable by any other cause, often more severe than it occurs in very serious diseases such as cancer and AIDS and debilitating to the extent that it causes a more than 50% reduction in work capacity and normal social relationships lasting more than 6 months.

According to the criterion in the Annals of International Medicine (December 1994), for this diagnosis, the patient must have four of the following eight symptoms persisting for more than 6 months:

1. neuropsychological disorders such as memory loss, excessive arousal, mental confusion, difficulty in thinking and concentration;

2. Faringitis;

3. palpable, soft cervical or axillary lymph nodes;

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4. muscle pain;

5. migrating athralgia without joint swelling;

6. undifferentiated headache of a type, nature and severity different from any headache the patient has previously experienced;

7. sleep disorders characterized by insomnia or hypersomnia or drowsiness;

8. undifferentiated tiredness and restlessness lasting 24 hours or more after physical exertion at a level previously readily tolerable.

It is well known that Parkinson's disease is generally regarded as a spontaneous condition, and that the symptoms of parkinsonism may result from the abuse of such agents as phenothiazine, butyrophenones and reserpine. Until now, Parkinsonism of drug addicts has been studied using meperidine-like compounds that synthesized MPTP and MPPP.

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP or NMPTP) and 1-methyl-4-phenyl-propoxypiperidine (MPPP) selectively break down dopaminergic neurons in Substantia nigra and induce other syndromes in humans and primates than the syndrome which, in terms of clinical, pathological and biochemical symptoms and their pharmacological response, is completely similar to spontaneous Parkinson's disease.

The similarity between spontaneous Parkinson's disease and MPTP-induced parkinsonism is so great that one can predict (Burns, et al .: The neuroxoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in monkey and man. Can. J. Neur. Sci., 11, No. 1 (supplement), 166-168, February 1984) that this induced parkinsonism may be more than a model. Parkinsonism induced by MPTP suggests a seemingly toxic cause of Parkinson's disease ”.

Alternative therapy for Parkinson's disease is based on levodopa (L-dopa) [i. (-) - 3- (3,4-dihydroxyphenyl) -2-aminopropanoic acid;

• · · · · · note. ] - a metabolic precursor of dopamine that itself is unable to cross the blood-brain barrier interface.

Since levo-dopa is extensively metabolized before it can reach the site of action in the brain, it must be administered at very high doses. L-dopa is therefore administered in combination with carbidopa, an inhibitor of dopecarboxylase, which prevents the systematic metabolism of levo-dopa before it reaches the brain.

When levodopa is administered alone, side effects such as anorexia, nausea and vomiting and orthostatic hypotension may occur, which may be countered by the concomitant administration of carbidopa.

After several months of L-dopa therapy, even in combination with a decarboxylation inhibitor, frequent complication side effects may occur: dyskinetic movements of the face, torso and limbs. The onset of such movements in most cases indicates that drug doses have reached a critical threshold, which must not be exceeded.

The above pathological conditions thus clearly show the need for a supportive or prophylactic or therapeutic substance which is mainly non-toxic and without side effects, and which can be safely used in a wide range, both in cases requiring simply an appropriate supplementary diet and onset of initial symptoms.

SUMMARY OF THE INVENTION

These multiple objectives - the production of a supportive, prophylactic and strictly therapeutic agent - can be achieved by a composition according to the invention which, as described in detail below, consists of a novel combination comprising L-carnitine or lower C ₂ to C ₆ alkanoyl-L-carnitine or a pharmacologically acceptable salt thereof; and

Nicotinamide adenine dinucleotide (NADH) or a precursor of NADH and / or a reduced form of nicotinamide adenine dinucleotide phosphate (NADPH).

Over the past decades since this basic discovery (Fritz, IB: 1968), that Lcarnitine was released by FC Gran, New York, Academic Press, pp. 39-63. is unique in its vital physiological role as a long-chain fatty acid transporter passing through the inner mitochondrial membrane into the mitochondrial matrix that is its oxidation site and since it was first discovered that primary L-carnitine deficiency (Engel and Angelini, Science, 179, 899 902 (1973) is the cause of serious, sometimes - albeit rarely - fatal forms of myopathy (accumulating lipid myopathy), in our knowledge of the pathological consequences of primary and secondary L-carnitine deficiency and, conversely, of therapeutic and nutritional value in its exogenous intake, great progress has been made.

Carnitine is present in all biological tissues at relatively high concentrations as free carnitine and at low concentrations in the form of acylcarnitines, which are metabolic products of the reversible reaction:

acyl CoA + carnitine θ acylcarnitine + CoASH catalyzed by three groups of enzymes, ie transferases, which differ from each other mainly in their excellent specificity for reaction substrates; they are: a carnitine acetyltransferase (CAT) group whose substrate is short-chain acyl groups (such as acetyl and propionyl); a carnitinoctanoyltransferase (COT) group, the substrate of which consists of medium chain acyl groups; and a carnitine palmitoyltransferase (CPT) group whose substrate has long chain acyl groups.

The important role of carnitine in intermediate metabolism with particular regard to its limited synthesis serves to explain how it can occur.

44 carnitine deficiency as a secondary phenomenon in various pathological functions involving different organs and systems. The widening of the clinical spectrum was reflected in the increased number of therapeutic opportunities that this natural compound exerts; the full extent and magnitude of these effects occurred when it was observed that L-carnitine replacement therapy dramatically reversed the clinical picture of patients suffering from accumulated lipid myopathy. The Food and Drug Administration (FDA) not only granted L-carnitine the status of 'orphan drug' but included it in its 'life-saving' list.

Advances in our knowledge of the pathological aspects of primary and secondary carnitine deficiency have been accompanied by a very rapid increase in the number of scientific and patent publications focusing mainly on L-carnitine and to a lesser extent on some acylcarnitines.

Pursuant to a partial search in the patent field, we teach that the use of Lcarnitine has been suggested in the cardiovascular field to treat cardiac arrhythmias and congestive heart failure (US 4,656,191), myocardial ischemia and myocardial anoxia (US 4,649,159); in the field of poor lipid metabolism, to treat hyperlipidemia and hyperproteinemia (US 4,315,944) and to normalize the abnormal HDL: LDL-VLDL ratio (US 4,255,449); in the field of total parenteral nutritional nutrition (US 4,254,147 and US 4,320,145); in nephrology against myasthenia and muscle cramp attacks caused by carnitine loss in the dialysate of chronic uremic patients undergoing regular hemodialysis (US 4,272,549); against toxic effects caused by antitumor agents such as adriamycin (US 4,400,371 and US 4,713,370) and halogenated anesthetics such as halothane (US 4,780,308); in the treatment of clogged vessels (US 4,415,589); against worsening of a large number of biochemical and other parameters in the elderly (US 4,474,812); for normalizing triglycerides and tumor necrosis factor (TNF-α) levels in AIDS patients and in asymptomatic HIV-positive patients (US 5,631,288).

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The use of L-carnitine has also been suggested in combination with other active ingredients such as the combination of L-carnitine with coenzyme Q10 with a wide range of metabolic and atherosclerotic effects (US 4,599,232).

With respect to alkanoyl-L-carnitines, the use of acetyl-L-carnitine is known from the treatment of central nervous system diseases, in particular Alzheimer's disease (US 4,346,107) and the treatment of diabetic neuropathy (US 4,751,242) where propionyl Lcarnitine has been proposed for the treatment of peripheral vasculopathy (US 4,343,816) and congestive heart failure (US 4,194,006).

The effect exerted by nicotinamide adenine dinucleotide coenzyme (NADH), whose role in the energy level is known, is also complex.

Its function in the respiratory chain is essential for the transport of electrons in the mitochondrial system and for the formation of ATP. Two NADH dehydrogenases were isolated from the internal mitochondrial matrix. One of lower molecular weight (mw = 78000), which appears to be a subunit of a larger complex (mw above 300000) and is considered to be a naturally occurring functional form of the system.

The various complexes situated within the mitochondrial membrane form a chain of oxidative systems known as cytochrome and coenzyme Q10, allowing electrons to transfer from a lower potential system to a higher potential system using oxygen and forming ATP. It is in fact a respiratory chain that results from oxidative phosphorylation that leads from NADH to ATP formation.

NADH together with cytochrome and coenzyme Q10 complexes are elements necessary for energy transformation to ATP, and NADH located at the beginning of this chain is the main element of this process.

The enzymatic function of NADH is no longer detectable in the formation of ATP in energetic type reactions, but NADH has also been shown to act as a coenzyme necessary for quinodihydroxypteridine reductase (DHPR) to continue biosynthesis of H4-biopterin.

Recently, the possibility of stimulating H4-biopterin biosynthesis and increasing its concentration in the brain has been suggested as a way to increase the concentration of L-dopa and hence dopamine, which is deficient in such diseases as parkinsonism, since it is observed that its deficiency is an element causing parkinson's neuropathy . While L-dopa can act as a precursor of dopamine and thus itself metabolically transform into this latter, it does not happen in the case of tyrosine, which may also be considered to be a precursor capable of producing Ldopa in the absence of tyrosine hydroxylase. In fact, individuals with parkinsonism have been found to decrease the concentration of this enzyme at the substantia nigra level. In addition, a decrease in the hydroxytyrosine concentration is accompanied by a strong decrease in the concentration of H4-biopterin, a coenzyme necessary for the synthesis of hydroxytyrosine. Since H4-biopterin does not penetrate the interface between blood and brain cells, and therefore H4-biopterin administration is of no importance, it seems appropriate to stimulate H4-biopterin production by administering the coenzyme necessary for the activity of quinodihydroxypteridine reductase (DHPR) causing H4-biopterin production. a function known to be performed by NADH. Thus, administration of NADH activates DHPR, resulting in the formation of the necessary tyrosine hydroxylase-activating H4-biopterin so that a new dopa synthesis is achieved.

Clinical trials based on intravenous administration of NADH to patients suffering from Parkinson's disease have confirmed the validity of these theoretical considerations presented herein and have shown a marked improvement in Parkinson's symptoms in treated subjects.

Mostly, oral administration of NADH in delayed-release gastrointestinal capsules has been avoided in order to avoid contact with acidic environments.

4

- 9 stomach, which would lead to a rapid decrease in the level of NADH, achieved comparable results.

Clinical improvement of Alzheimer's disease and chronic fatigue syndrome (CFS) with NADH has also been reported (Birkmayer, J.G., Annals Clin. Lb. Sel., 26, 1, 1996).

Based on the above characteristics of the compounds, the possible interaction between these compounds was investigated by performing a series of tests with a combination of Lcarnitine or its alkanoyl derivatives and NADH and / or NADPH. Surprisingly, synergistic interactions between the components of these combinations were observed when performing these tests with novel combinations, which could not be predicted based on our pharmacological knowledge of L-carnitine or its alkanoyl derivatives and NADH and NADPH.

The composition according to the invention consists of the following components in combination:

(a) L-carnitine or alkanoyl-L-carnitine in which the straight or branched chain of the alkanoyl group has 2-8, preferably 2-6 carbon atoms, or one of their pharmacologically acceptable salts;

(b) NADH and / or NADPH or a precursor of NADH; and (c) a pharmacologically acceptable excipient.

The NADH precursor was preferably nicotinamide.

The weight ratio of (a) to (b) was generally in the range from 1: 0.01 to 1: 1 and preferably ranges from 1: 0.05 to 1: 0.5, so that the weight ratio can be, for example, 1: 0 , 1.

The alkanoyl-L-carnitine is preferably selected from the group consisting of acetyl-L-carnitine, propionyl-L-carnitine, butyryl-L-carnitine, valeryl-L-carnitine and isovaleryl-L-carnitine. Particularly preferred are acetyl L-carnitine and propionyl L-carnitine.

* * · · · · · · ······

For the purposes of the present invention, acetyl-L-carnitine, propionyl-L-carnitine, butyryl-L-carnitine, valeryl-L-carnitine and isovaleryl-L-carnitine are compounds in the form of intrinsically complex salts.

By pharmacologically acceptable salt of L-carnitine or alkanoyl-L-carnitine is meant any acid salt of these compounds which does not give rise to undesired toxic or side effects. These acids are well known to pharmacologists and pharmacists.

Examples of such salts include, but are not limited to: chloride, bromide, iodide, aspartate, acid aspartate, citrate, acid citrate, tartrate, phosphate, acid phosphate, fumarate, acid fumarate, glycerophosphate, glucophosphate, lactate, maleate, acidic maleate, orotate, oxalate, acid oxalate, sulfate, sulfate, trichloroacetate, trifluoroacetate, and methanesulfonate.

A list of FDA approved pharmacologically acceptable salts can be found in Int. J. Pharm., 33, 201-217, 1986, which is incorporated herein by reference.

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

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

For the sake of simplicity, only the combinations of L-carnitine and NADH will be mentioned hereinafter, but it should be understood that combinations of L-carnitine and NADPH or the above-mentioned alkanoyl-Lcarnitines and NADH and / or NADPH are equally effective to achieve the effects of the invention.

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- 11 Toxicological tests

It is known that carnitine and NADH have only limited toxicity and are well tolerated. These excellent characteristics were confirmed by intravenous administration to both rats and mice in combinations of up to 100 mg.kg ^-1 L-carnitine and 5 mg.kg ^-1 NADH. In a prolonged toxicological test (30 days), oral administration of a combination of 250 mg.kg ^-1 L-carnitine and 10 mg.kg ^-1 NADH was well tolerated and no mortality, toxicity or intolerance was observed in the test animals. Blood analysis and histological tests performed on different organs at the end of the test did not show any abnormalities when compared to control animals, thus confirming the good tolerability of the study combination.

Muscle Enzyme Enhancement After Extended Load To evaluate the dependence of carnitine and NADH as well as the combination of both on the concentration of mitochondrial enzymes contained in stressed muscles, tests were performed to determine whether the activity of these mitochondrial muscles could be increased under prolonged loading enzymes in response to the increased energy consumption required by prolonged muscle load compared to control animals. For this purpose, a group of rats of Wistar breed exposed muscle exercise their location on the device Rotaroid (Basel, Como, Italy) at a rate of 20 m.min ^-1 for 120 min every day (Benzi G., J. Appl. Physiol. 38, 565 (1975). Muscle enzyme activity was determined after seven or thirty days of exercise by subsequent isolation and homogenization of the gastrocnemius muscle in all rats (Oscai, LB, J. Biol. Med., 245, 6968, 1971). The enzymes examined were citrate synthetase, isocitrate dehydrogenase and succinate dehydrogenase.

The results obtained with this assay showed that the combination of carnitine and NADH was capable of inducing a very significant increase in enzyme activity after only seven days of exercise, whereas there was no change in this observation period for carnitine or NADH alone when compared to control animals.

Strong synergistic effect of these exercises.

- 12 of the two substances were even more noticeable after 30 days

Substance administered Day Citrate synthetase Isocitrate Amber exercises dehydrogenase dehydrogenase Checklist 0 20.9 ± 1.4 2.25 ± 0.31 3.70 ± 0.22 Checklist 7 22.1 ± 1.6 2.30 ± 0.20 3.90 ± 0.19 Checklist 30 29.9 ± 2.1 3.33 ± 0.20 5.20 ± 0.30 Carnitine 250 mg.kg- ¹ 0 20.8 ± 0.95 3.05 ± 0.19 3.35 ± 0.35 Carnitine 250 mg.kg- ¹ 7 22.6 ± 1.9 2.85 ± 0.31 3.85 ± 0.45 Carnitine 250 mg.kg ¹ 30 30.1 ± 0.95 2.98 ± 0.16 4.90 ± 0.33 NADH 10 mg / kg ¹ 0 21.5 ± 1.4 2.35 ± 0.29 3.60 ± 0.21 NADH 10 mg / kg ¹ 7 30.5 + 2.5 3.65 ± 0.55 4.15 ± 0.45 NADH 10 mg / kg ¹ 30 33.6 ± 2.1 3.55 ± 0.36 5.40 ± 0.45 Carnitine 250 mg. kg ¹ -U 0 21.4 ± 1.9 2.15 ± 0.18 3.80 ± 0.22 T NADH 10 mg / kg ¹ Carnitine 250 mg.kg ¹ _L 7 47.7 ± 3.92 5.1 ± 0.29 7.15 ± 0.30 1 NADH 10 mg / kg ¹ Carnitine 250 mg.kg- ¹ 30 75.9 ± 3.51 6.3 ± 0.5 9.25 ± 0.65

NADH 10 mg.kg (*) Enzymatic activity is expressed as gmol of substrate used per min.g ^-1 tissue weight.

Test for Increasing ATP Concentrations in Rabbit Papillary Muscle after Hypoxia These tests were used to determine whether L-carnitine and NADH or a combination of both are able to maintain ATP concentrations in rabbit papillary muscle after undergoing hypoxia known to lead to depletion of this energy. compounds. Tests were conducted on rabbits from New Zealand who

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13 received injections of both L-carnitine (100 mg.kg- ¹ ) and NADH (10 mg.kg- ¹ ) individually, as well as both agents in combination, every day for three consecutive days.

Another group of animals served as a control group and received no preparations. At the end of the third day of administration, all animals were sacrificed, their hearts removed, and papillary muscle sections of 1 mm in diameter with thickness were prepared.

4.5 mm. Tissues so isolated were washed in a thermostatic bath with 100% saturated O ₂ solution. Experimental hypoxia was then performed by introducing 100% N ₂ instead of O ₂ into the bath. The ATP content in the papillary muscle was determined 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 samples maintained under normal washing for 90 min. and after hypoxia lasting 90 min.

These tests showed that ATP concentrations were significantly reduced in both control animals and animals treated with carnitine alone or NADH alone. Conversely, animals treated with a combination of carnitine and NADH were found to be fully protected against the reduction in ATP levels caused by hypoxia.

Thus, these tests were able to demonstrate the ability of the combination of L-carnitine and NADH to protect the ATP present in the papillary muscle from a reduction in the concentration induced by hypoxia that was not achieved by L-carnitine alone or NADH alone; this was surprisingly achieved by combining them.

Substance administered ATP concentration (mol.g ^-1 tissue) before hypoxia after hypoxia Checklist 1.54 ± 0.31 0.40 ± 0.051 Carnitine 100 mg.kg- ¹ 1.65 + 0.28 0.55 ± 0.031 NADH 10 mg.kg ^-1 1.60 ± 0.30 0.65 ± 0.044 Carnitine 100 mg.kg ¹ + 1.90 ± 0.37 1.52 ± 0.061 NADH 10 mg.kg ^-1

- 14 * 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9999 9999 9999

Test of the ability of L-carnitine and NADH to stimulate dopamine production.

These tests were performed on cultures of neuroblastoma cells with a cell concentration ranging from 15-30 into 60,000,000 incubated with 200 pg.ml ^-1 NADH or 2 mg.ml ^-1 L-carnitine or with the two components in combination.

NADH and L-carnitine induced dopamine formation was tested by high pressure liquid chromatography by the Mayer method (Mayer, GS, Strong, RF, Current separation, 4, 44, 1982) modified by Jonsson and Keller (Jonsson, G., Holman, H., Adams, RN, Central Adrenaline Neurones, Ed De Fuxe - Pergamon Press, 59, 1980; Keller, R., Oke, A., Mefford, I., Life Sciences, 19, 995, 1976). The results of these tests show that the addition of NADH to the cell culture effectively induces an increase in dopamine production corresponding to the number of cells present.

A considerably greater increase can be obtained if NADH solution is added to L-carnitine, which itself causes only a very weak effect. Thus, a synergistic effect can also be observed in this test.

Percentage increase in dopamine synthesis in cell cultures of neuroblastomas incubated with NADH or carnitine as a function of the number of cells incubated (in millions)

Substance administered Number % Number % Number % cells increase cells increase cells increase NADH 100 pg.ml ^-1 (millions) 15 Dec 4,5 (millions) 30 31.5 (millions) 60 45.5 200 NADH pg.mí ^-1 15 Dec 11.8 30 40.6 60 55.6 Carnitine 1 mg.ml ^-1 15 Dec - 30 2.1 60 5.6 Carnitine 2 mg.ml ^-1 15 Dec - 30 3.3 60 6.6 NADH 100 pg.ml ^-1 15 Dec 6.6 30 45.2 60 50.6 + Carnitine 1 mg.ml ^-1 NADH 200 pg.ml ^-1 15 Dec 18.4 30 56.4 60 70.5

+ Carnitine 2 mg.ml ^-1

MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyriclin) assay.

The use of MPTP as a neurotoxin mainly active at the level of the neuroskeletal system may be an important experimental model in the study of parkisonism and its biochemical and clinical pathogenesis.

In both monkeys and mice, high doses of MPTP (40 mg.kg ^-1 ) induce hypokinetic and bradykinetic symptoms typical of Parkinson's disease accompanied by a marked decrease in dopa and its metabolites. In these assays, it was investigated whether the behavioral and mobility impairment induced in MPTP mice, as well as dopamine concentrations, could be corrected and corrected by administering NADH or L-carnitine alone or both in combination.

C57 BE / 6 breeding black mice weighing 20 g were used for these tests; one group of these mice was treated as a control and the other group was injected subcutaneously twice at 40 mg.kg ^-1 MPTP at a 24 hour interval. Three weeks after the MPTP injection, the motility of all animals, including control animals, was evaluated. After three weeks a dopa test was also performed. Both NADH and carnitine were administered immediately prior to the commencement of the mobility test; mobility was monitored in a plexiglass box crossed at different heights by two infrared beams as described by Archer (Archer, T., Fredrikson, A., Psychopharmacology, 88, 141, 1986).

MPTP-induced mobility decreased by more than 80% of the control mice and reduced mobility by 60% and 70% was found in NADH alone and L-carnitine alone, whereas in both combinations the mobility returned to virtually the original level (20% reduction). Also interesting were the levels of dopa in the striated muscle, which was reduced by 90% in control mice receiving MPTP, but near normal levels were seen in mice receiving the preparations. Again, in these tests, the effect of Lcarnitine alone proved negligible and was 40% for NADH; the combination returned dopa to a level very close to the concentrations normally present in the tissues present.

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44

Some examples of formulations of the invention are given below:

(1) Internal complex salt of L-carnitine NADH mg mg 200 5 (2) Internal complex salt of L-carnitine mg 200 NADH mg 10 (3) Internal complex salt of acetyl-L-carnitine mg 250 NADH mg 5 (4) Internal complex salt of acetyl-L-carnitine mg 500 NADH mg 10 (5) Propionyl-L-carnitine inner complex salt mg 250 NADH mg 5 (6) Internal complex salt of L-carnitine mg 200 NADH mg 5 Coenzyme Q10 mg 20 May Pyridoxin mg 3 Selenium mg 20 May Zinc mg 2 (7) Internal complex salt of L-carnitine mg 200 NADH mg 5 Coenzyme Q10 mg 20 May Taurin mg 10 Inosin mg 100 ALIGN! Creatine mg 100 ALIGN! Pyruvic acid mg 10

Claims (12)

Patent claims 1. A composition comprising: (a) L-carnitine or alkanoyl L-carnitine, the alkanoyl group of which has a straight or branched chain of 2 to 8, preferably 2 to 6, carbon atoms, or a pharmacologically acceptable salt thereof; (b) a reduced form of nicotinamidadenine dinucleotide (NADH) or a precursor thereof, and / or a reduced form of nicotinamidadenine dinucleotide phosphate (NADPH); and (c) a pharmacologically acceptable excipient. 2. A composition according to claim 1 wherein the NADH precursor is nicotinamide. Composition according to claim 1 or 2, characterized in that the weight ratio (a): (b) ranges from 1: 0.01 to 1: 1. 4. A composition according to claim 3 wherein the weight ratio (a): (b) is in the range of from 1: 0.02 to 1: 0.2. Composition according to claim 4, characterized in that the weight ratio (a) :( b) is 1: 0.1. 6. A composition according to claims 1 to 5 wherein the alkanoyl L-carnitine is selected from the group consisting of acetyl L-carnitine, propionyl L-carnitine, butyryl L-carnitine, valeryl L-carnitine and isovaleryl-L. -carnitine. Composition according to any one of the preceding claims, characterized in that the pharmacologically acceptable salts are selected from the group consisting of: chloride, bromide, iodide, aspartate, acid aspartate, citrate, acid citrate, tartrate, phosphate, acid phosphate, fumarate, acid fumarate, glycerophosphate, glucophosphate, lactate, maleate; - 18 acid maleate, orotate, oxalate, acid oxalate, sulphate, acid sulphate, trichloroacetate, trifluoroacetate and methanesulphonate. Composition according to any one of the preceding claims, characterized in that it further comprises vitamins, coenzymes, minerals and antioxidants. Composition according to claim 1 or 2, characterized in that the unit dosage form contains 100 to 500 mg of (a) L-carnitine or alkanoylcarnitine or an equivocal amount of their pharmacologically acceptable salt and such an amount of (b) NADH, NADH or NADPH precursor to the weight ratio (a): (b) ranged from 1: 0.01 to 1: 1. 10. A composition according to claim 4 wherein the unit dosage form comprises 100 to 500 mg of (a) L-carnitine or alkanoyl carnitine or an equivalent amount of their pharmacologically acceptable salt and such an amount of (b) NADH, NADH or NADPH precursor to give a weight ratio of (and); (b) ranged from 1: 0.02 to 1: 0.2. Composition according to any one of the preceding claims, characterized in that it is in a form suitable for oral administration and in the form of a supplementary food. Composition according to any one of the preceding claims, characterized in that it is in the form of a medicament for oral or parenteral administration.