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

Composition comprising L-carnitine or an alkanoyl L-carnitine and NADH and/or NADPH Download PDF

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CN1299283A
CN1299283A CN99805644A CN99805644A CN1299283A CN 1299283 A CN1299283 A CN 1299283A CN 99805644 A CN99805644 A CN 99805644A CN 99805644 A CN99805644 A CN 99805644A CN 1299283 A CN1299283 A CN 1299283A
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carnitine
nadh
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C·卡瓦加
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Sigma Tau HealthScience SpA
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    • A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
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    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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    • A—HUMAN NECESSITIES
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    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

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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

The compositions that comprises L-carnitine or alkanoyl L-carnitine and NADH and/or NADPH
The present invention relates to a kind of compositions, by the booster action to periphery muscle and central nervous system's level, both metabolism and the energy to skeletal muscle showed, also muscular movement and coordinative role adjusting played a role on the maincenter level for it.Therefore, said composition can be taked the mode of food additive or real medicine and bring into play its effect, and this is different because of its support or preventive effect or strict therapeutical effect, and said composition plays a role at the particular individual of being used.
Exactly, as food additive or preventive, the present composition is particularly suitable for promoting being engaged in the adaptation of the individual skeletal muscle of long-time physical exertion, also be suitable for resisting weakly people's muscle fatigue and sensation tired out, even he is not engaged in the physical exertion more or less of any way fully.
Be the maximum adaptation that the people that is engaged in occupation or sparetime sports wishes to reach at short notice skeletal muscle, keep the long period as much as possible then, with physical exertion that can be for a long time.May cause the improper use, particularly steroid of medicine to the demand of this optimal adaptation state.People know this class medicine can increase proteinic synthetic, thereby strengthen the growth of muscle quality, its degree substantially exceeds the effect that training and diet are reached.But, the use of these medicines is illegal, and is also deleterious beyond doubt to occuptional movement.
Obviously, unique approach that by rights achieves the above object is to carry out suitable training program, and in conjunction with suitable diet, diet is strengthened by adding suitable food additive.
The term here " weakness " implication is the nonspecific symptom that extensively exists, be the heavy characteristics of living burden, be popular in main metropolis and busy section of town at present, relate to populous, how irrelevant with factors such as age and social statuss, it is characterized in that muscle strength shortage or forfeiture, be easy to fatigue and insufficient to the reaction of stimulation.
When being used as strict therapeutic agent, concrete an application of the present composition is treatment chronic fatigue syndrome and parkinson, and by taking the symptom that is similar to spontaneous parkinson that the guiding drug of violating a ban rises.
Chronic fatigue syndrome (CFS) formally is described in " internal medicine yearbook 1988 " first, it be a kind of be the disease of feature with agnogenic to a certain degree tired, it is tired that its intensity often substantially exceeds very serious disease finding such as tumor and AIDS, debilitating degree causes work activities and normal social relations to reduce more than 50%, continues more than 6 months.
According to the CFS diagnostic criteria that " internal medicine yearbook " (in December, 1994) described, the patient must possess in following eight kinds of symptoms at least four kinds, and continue above 6 months:
1, neuropsychology disease, for example the loss of memory, irritability are too high, mental disorder, thinking and wholwe-hearted difficulty;
2, pharyngitis;
3, the neck that can touch a tender spot or axillary lymph nodes;
4, myalgia;
5, migration arthralgia, but without any arthroncus;
6, diffuse headache, its type, feature and seriousness all are different from the ill preceding headache of patient;
7, the sleep disease is a feature with insomnia or hypersomnia or drowsiness;
8, continued after the physical exertion 24 hours or above universality tired and uncomfortable, and formerly stand easily.
Parkinson is generally considered to be a kind of autonomous state, and people know the parkinson symptom and can be caused by drug dependence by this, for example phenothiazine, butyrophenone and reserpine.Recently, the drug abuser's parkinson that self-injection is similar to the chemical compound of Pethidine is studied, synthetic MPTP and the MPPP of obtaining of the abuse of Pethidine.
In fact, 1-methyl-4-phenyl-1,2,3, dopaminergic neuron in 6-tetrahydropyridine (MPTP or NMPTP) and 1-methyl-4-phenyl-propoxyl group-piperidines (MPPP) selective destruction black substance, both to the people, also to the primates except that the people bring out clinical, pathology and biochemical aspect and all be quite analogous to spontaneous symptoms of Parkinson's Disease on the pharmacological reaction.
Similarity between the parkinson that spontaneous parkinson and MPTP-bring out is so big, so that there is the people to suppose (Burns etc.: 1-methyl-4-phenyl-1,2,3, the 6-tetrahydropyridine is to monkey and people's neurotoxicity " Canadian Journal of Neuroscience " 11, n.1 (supplementary issue), 166-168, in February, 1984), " what may construct is not only a model to this parkinson of being brought out.The parkinson that MPTP-brings out has been pointed out a parkinsonian toxicity cause of disease of inferring ".
Be used to control parkinsonian selection therapy and be based on levodopa (L-DOPA) administration at present, it is the metabolic precursor thereof of dopamine, and itself can not cross blood-brain barrier.
Because by fully metabolism, it should be with very high dosed administration before it can arrive site of action in the brain for levodopa.So L-DOPA and carbidopa administering drug combinations, the latter is a kind of dopa decarboxylase inhibitor, and it prevents the general metabolism of levodopa before arriving brain.
When levodopa is individually dosed, side effect may take place, for example anorexia, feel sick, vomiting and orthostatic hypotension, but, in case also administration of carbidopa, these symptoms can be alleviated basically.
But, behind L-DOPA treatment some months, even when combining with the decarboxylation inhibitor, also undesirable side effect may take place frequently: the dyskinesia of face, trunk and extremity.As a rule, dyskinetic generation explanation drug dose has reached the threshold limit value that must be able to not surpass.
Therefore, press for a kind of support/preventing/treating agent, as its curative effect, the nontoxic and result that has no side effect basically, both need suitable food additive simply, also under the situation of the initial symptom that above-mentioned pathological state takes place, can both be by user security ground use widely.
These a plurality of targets--provide a kind of supportive, preventative and strict therapeutic agent--and are realized by the present composition; just as the following detailed description; said composition is a kind of combination of novelty; wherein comprise L-carnitine or rudimentary C2-C6 alkanoyl L-carnitine or its pharmaceutically acceptable salt as basis, also comprise the reduction form (NADPH) of nicotinamide adenine dinucleotide (NADH) or NADH precursor and/or nicotinamide-adenine dinucleotide phosphate salt.
In the past few decades, (Fritz.I.B.: " carnitine is to the metabolism consequence of the influence of long-chain fatty acid Oxidation " F.C.Gran compiles in a basic discovery, New York, Academic Press, 1968, pp.39-63) be, the unique distinction of L-carnitine is to serve as long-chain fatty acid and passes mitochondrial membrane and enter mitochondrial matrix, just this important physical effect of carrier at the position of Oxidation takes place in them, because this discovery, also owing at first thinking (Engel and Angelini " science " 1973,179:899-902) constitutional L-carnitine shortage is the inducement of severe form myopathy (lipid storage myopathy), although this disease is rare, sometimes also be fatal, therefore, as far as our knowledge goes, on the pathological consequences of constitutional and Secondary cases L-carnitine shortage, obtained major progress, on the contrary, the treatment of exogenous supply L-carnitine and nutritive value are not but made progress.
Carnitine exists the free carnitine of high concentration and the acylcarnitines of low concentration in all biological tissue, the latter is the metabolite of following reversible reaction: acyl-CoA+carnitine acylcarnitines+CoASH
This reaction is by three groups of enzyme catalysiss, i.e. transferring enzyme, and mainly rely on them that the specificity of enzyme reagent substrate is distinguished: carnitine acetyltransferase (CAT), its substrate are short chain acyl (for example acetyl group and propionos); Carnitine decoyl transferring enzyme (COT), its substrate comprises middle chain acyl; And carnitine palmitoyltransferase (CPT), its substrate comprises long acyl.
Carnitine can explain that in the important function of intermediate supersession, particularly about its limited biosynthesis how as the secondary incident carnitine taking place in relating to the various pathology functions of Different Organs and system lacks.The expansion of clinical scope has reflected the increase of the therapy apparatus meeting relevant with this native compound curative effect; Reverse lipid dramatically when storing myopathy patient's clinical manifestation when people observe L-carnitine alternative medicine, disclosed the overall range and the amplitude of this curative effect.FDA Food and Drug Administration (FDA) not only gives the status of L-carnitine " medication separately " (orphan drug), and it is included in the tabulation of " lifesaving " medicine.
As far as our knowledge goes, emerged a large amount of scientific papers and patent gazette about the progress on the pathological significance of constitutional and Secondary cases carnitine shortage, they are primarily aimed at the L-carnitine, seldom at some acylcarnitines.
According to our incomplete investigation to the patent situation, there is the people to propose the L-carnitine is used in cardiovascular field, be used for the treatment of arrhythmia and congestive heart failure (US4656191), myocardial ischemia and myocardium hypoxia (US 4649159); Be used in lipid metabolism disease field, be used for the treatment of hyperlipemia and hyperlipoproteinemia (US 4315944), be used to correct HDL:LDL-VLDL abnormal proportion (US 4255449); Be used in overall parenteral absorption field (US4254147 and US 4320145); In nephrology, be used for resisting the chronic uremia patient who accepts regular hemodialysis and lose myasthenia and the muscular cramp outbreak (US 4272549) that causes by the dialysis solution carnitine; Be used to resist toxic action (US 4400371 and US 4713370) that brings out by anticarcinogen such as amycin and the toxic action (US 4780308) that brings out by halogenated anesthetics such as halothane; Be used for the treatment of venous stasis (US 4415589); Be used to resist a large amount of biochemical and behavioral indicator declines (US 4474812) of old people; Be used to correct the triglyceride and tumor necrosis factor (TNF-α) level (US5631288) of AIDS patient and asymptomatic HIV-positive patient.
The somebody has proposed L-carnitine and other active component are united use, for example has the L-carnitine coenzyme Q10 (US4599232) of wide spectrum metabolism/study of anti-atherogenic effect.
As for alkanoyl L-carnitine; acetyl L-carnitine becomes known for treating central nervous system disease; Alzheimer (US 4346107) particularly; be used for the treatment of diabetic neuropathy (US 4751242), and propionyl L-carnitine peripheral vascular disease (US4343816) and congestive heart failure (US 4194006) have been used to treat.
Complicated equally is that it acts on the energy level knows by the activity of coenzyme nicotinamide adenine dinucleotide (NADH) performance.
Its function in respiratory chain is necessary to the chondriome electron transport of ATP in forming of unifying.People have isolated two kinds of nadh dehydrogenases the substrate in mitochondrion.Small-molecular weight person (M.W.78000) is likely that it is considered to the functional form of the natural origin of this system than the macrocomplex subunit of (M.W. surpasses 300000).
Each species complex that is arranged in mitochondrial inner membrane has been formed a series of oxidative systems, and its name is called cytochrome and coenzyme Q10 chain, utilizes the formation of oxygen and ATP, allows electronics to be transported to the high potential system from the electronegative potential system.In fact, oxidative phosphorylation causes from NADH to produce ATP from respiratory chain.
NADH and cytochrome and coenzyme Q10 complex are the essential elements that energy transforms to ATP, and the NADH that is found when this chain begins is the main adjusting element of this process.
The enzyme function of NADH not only can be detected in the kind of energy reaction that forms ATP, and has shown that recently NADH serves as a kind of coenzyme, and the biosynthesis that quinine dihydroxy-pteridine reductase (DHPR) is carried out the H4-biopterin is necessary.
Thereby it is to increase a kind of approach that the L-DOPA increases dopamine that the probability that stimulates the biosynthesis of H4-biopterin and increase concentration in its brain is suggested recently, they lack in diseases such as parkinson, and this shortage is considered to the neuropathic basis of parkinson characteristic of disease.Though the L-DOPA can serve as dopamine precursor, can be converted into the latter by metabolism, do not have the tyrosine hydroxylase in the presence of, this conversion does not take place in tyrosine, although it also can be considered to cause the precursor that the L-DOPA forms.In fact found on parkinsonian's black substance level that this kind of enzyme has reduced.And the minimizing of hydroxyl tyrosine will be followed the remarkable minimizing of H4-biopterin, and the latter is necessary coenzyme to synthesizing of hydroxyl tyrosine.Because the H4-biopterin is not crossed blood-brain barrier, therefore the direct administration of H4-biopterin is otiose, by contrast, it is seemingly useful to appeal to the stimulation that the H4-biopterin is formed, to be necessary coenzyme administration to the activity of quinine dihydroxy-pteridine reductase (DHPR) formation H4-biopterin just, the formation of H4-biopterin is known to be the function of being finished by NADH.Therefore, the NADH administration activates DHPR, causes the formation of H4-biopterin, H4-biopterin and then be necessary to activating the tyrosine hydroxylase, thus realize the new synthetic of DOPA.
Based on NADH the effectiveness that above-mentioned theory is supposed has been confirmed in the clinical trial of parkinsonian's intravenous administration, the patient's that treats parkinson disease symptoms is significantly improved.
Oral administration NADH has obtained roughly suitable result, notes using the gastrointestinal type capsule that postpones to discharge to carry out administration, causes the rapid reduction of NADH level with the sour environment of avoiding stomach.
The clinical improvements that the NADH administration obtains Alzheimer and chronic fatigue syndrome (CFS) also has report (Birkmayer J.G., " clinical laboratory's science yearbook " 26,11996).
According to the feature of above-claimed cpd, interactional probability takes place between them by a series of test assessments, test is carried out at the combination of L-carnitine or its alkyl acyl derivative and NADH and/or NADPH.By the test of carrying out at the combination of these novelties; observed wondrous and unexpected concertedness and interact between each component of this combination, this is unpredictable fully on our the pharmacology's Knowledge Base about L-carnitine or its alkyl acyl derivative and NADH and NADPH.
The present composition comprises the following component that mutually combines:
One of (a) L-carnitine or a kind of alkanoyl L-carnitine, wherein this straight or branched alkanoyl has 2-8, is preferably 2-6 carbon atom, or their pharmaceutically acceptable salts;
(b) NADH or NADH precursor and/or NADPH; With
(c) pharmaceutically acceptable excipient.
Preferably, this NADH precursor is a nicotiamide.
(a) with (b) weight ratio generally from 1: 0.01 to 1: 1, should be preferably 1: 0.05 to 1: 0.5; For example, weight ratio can be 1: 0.1.
Alkanoyl L-carnitine should preferably be 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.Acetyl L-carnitine and propionyl L-carnitine are particularly preferred.
For purposes of the present invention, the implication of L-carnitine, acetyl L-carnitine, propionyl L-carnitine and isovaleryl L-carnitine is the interior salt form of these chemical compounds.
The implication of the pharmaceutically acceptable salt of L-carnitine or alkanoyl L-carnitine is these chemical compounds and the sour formed salt arbitrarily that can not cause unwanted toxicity or side effect.These acid are known pharmacologist and pharmacy expert.
The limiting examples of salt is: 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; Trifluoroacetate and mesylate.
The tabulation of the pharmaceutically acceptable salt of FDA permission can be at " Inpharm magazine " 33, and (1986) are found among the 201-217, quote at this as a reference.
The present composition can further comprise vitamin, coenzyme, mineral and antioxidant.
In unit dosage forms; the present composition for example comprises 100-500mg's (a) L-carnitine or a kind of alkanoyl L-carnitine; one of or their pharmaceutically acceptable salts of equivalent; (b) NADH or NADPH with constant weight; make (a) and weight ratio (b) from 1: 0.01 to 1: 1, be preferably 1: 0.02 to 1: 0.2.
For for simplicity, will only relate to the combination of L-carnitine and NADH below, but self-evidently be, the combination of L-carnitine and NADPH or above-mentioned alkanoyl L-carnitine and NADH and/or NADPH is effectively same, thereby intactly reaches the object of the invention.
Toxicology test
Known carnitine and NADH only have limited toxicity, and toleration is good.To confirm the feature that these are desirable up to the combination of 100mg/kg L-carnitine and 5mg/kg NADH to administration in rat and the mouse vein.In long-term (30 days) toxicity test, the 250mg/kgL-carnitine is can be well tolerable by the treatment animal with the oral administration that 10mg NADH makes up, and has not both produced lethal or toxicity, has not also produced the sign of intolerance.Hematochemistry and the histological examination of carrying out each organ after treatment finishes disclose, and compare with control animal not unusually, thereby have confirmed that the combination of being studied has good tolerability.
The increase test of long-time movable back muscle enzyme
In order to assess carnitine and NADH and both combinations influence to the cyclophorase concentration of participation musculation, test, whether to some extent increase, make great efforts required than the macro-energy demand to satisfy long-time muscle with these mitochondria enzyme activities in the rat gastrocnemius of determining to carry out long-time musculation if can compare according to animal.One group of Wistar rat is carried out muscular training, and method is to place them in the Rotaroid instrument that speed is 20m/min (Basile, Como, Italy) last 120 minute (Benzi G., " applied physiology magazine " 38,565,1975) every day.Train after seven days or 30 days and to separate and the gastrocnemius of every rat of homogenize, assess the activity (Oscai L.B., " biomedical magazine " 245,6968,1971) of muscle enzyme.The enzyme of being assessed is citrate synthetase, Isocitrate dehydrogenase and succinate dehydrogenase.
This test gained is the result prove, the training that is combined in of carnitine and NADH only just can the inducible enzyme activity significantly increase after seven days, and in this observing time, what variation list has not detected compared with the control with carnitine or NADH.
The strong synergism of these two kinds of products even more obvious after 30 days in training. 0 20.9±1.4 2.25±0.31 3.79±0.22 7 22.1±1.6 2.30±0.20 3.90±0.19 30 29.9±2.1 3.33±0.20 5.20±0.30250mg/kg 0 20.8±0.95 3.05±0.19 3.35±0.35250mg/kg 7 22.6±1.9 2.85±0.31 3.85±0.45250mg/kg 30 30.1±0.95 2.98±0.16 4.90±0.33 NADH 10mg/kg 0 21.5±1.4 2.35±0.29 3.60±0.21 NADH 10mg/kg 7 30.5±2.5 3.65±0.55 4.15±0.45 NADH 10mg/kg 30 33.6±2.1 3.55±0.36 5.40±0.45250mg/kg 0 21.4±1.9 2.15±0.18 3.80±0.22+NADH 10mg/kg250mg/kg 7 47.7±3.92 5.1±0.29 7.15±0.30+NADH 10mg/kg250mg/kg 30 75.9±3.51 6.3±0.5 9.25±0.65+NADH 10mg/kg
(*) enzymatic activity is represented with the μ mol of the used substrate of every min/g tissue weight
The increase of rabbit papillary muscles ATP concentration test behind the hypoxia
Utilize these test assessments L-carnitine and NADH or both to be combined in to make the ATP concentration that whether can keep the rabbit heart papillary muscles behind the rabbit hypoxia, known hypoxia can cause the consumption of this energy chemical compound.New zealand rabbit is tested, and animal is accepted independent L-carnitine (100mg/kg) and the intravenous injection of NADH (10mg/kg) every day, and the intravenous injection of these two kinds of combinations of substances, continuous three days.
Another treated animal served as control group is not received treatment.After treating end in the 3rd day, put to death all animals, take out heart, separate the papillary muscles section of diameter 1mm, thick 4.5mm.The isolating perfused tissue of institute is being equipped with 100% saturated O 2In the temperature chamber of solution.In temperature chamber, add 100%N then 2Replace O 2, cause experimental hypoxia.Utilize the described method of Strehler B.L. (Strehler B.L. " Enzymology method III " New York.Acad.Press, 871,1957) to analyze the ATP content of papillary muscles.All analyze remaining on following 90 minutes of normal perfusion and the tissue samples of lasting hypoxia after 90 minutes.
These test demonstration, and control animal and single ATP concentration with carnitine or single animal with the NADH treatment have all reduced basically.On the other hand, in the animal of the combined therapy of using carnitine and NADH, found to resist the complete protective effect of the ATP minimizing of bringing out by hypoxia.
The ATP that these combined protections of testing so can disclosing L-carnitine and NADH are present in the papillary muscles resists the ability of the minimizing of being brought out by hypoxia; its degree of protection is that list is beyond one's reach with NADH with L-carnitine or list; surprisingly, this combination can reach.ATP concentration (mol/g tissue)
Behind the preceding hypoxia of treatment hypoxia
Contrast 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 ability test that L-carnitine and NADH stimulate dopamine to produce
The neuroblastoma cell culture of cultivating with the combination of 200 μ g NADH/ml or 2mg/ml L-carnitine or these two kinds of components is carried out these tests, and cell concentration is 1,000,000 of 15-30 to 60.
Method (Mayer G.S. according to Mayer, Strong R.F., Currentseparation 4,44, and 1982) produce by the dopamine that NADH and L-carnitine bring out by HPLC mensuration, this method is through improvement (the Jonsson G. of Jonsson and Keller, Holman H., Adams R.N., " maincenter epinephrine neuron " Ed.De Fuxe-Pergamon Press, 59,1980; Keller R., Oke A., Mefford I., " life sciences " 19,995,1976).These result of the tests prove, add the generation that NADH effectively increases dopamine in cell culture, and it is relevant with cell quantity.
When in NADH solution, adding the L-carnitine, can obtain significant increase, and list only produces slight effect with the L-carnitine.Therefore, synergism also is tangible in these trials.
With the synthetic increase percentage rate of dopamine in neuroblast oncocyte (N.cells) culture of NADH or carnitine cultivation, be that the function treatment N.cells of institute's cultured cell number (1,000,000) increases % N.cells increase % N.cells increase %
(1,000,000) (1,000,000) (1,000,000) NADH 100 μ g/ml 15 4.5 30 31.5 60 45.5 NADH 200 μ g/ml 15 11.8 30 40.6 60 55.6 carnitine 1mg/ml 15-30 2.1 60 5.6 carnitine 2mg/ml 15-30 3.3 60 6.6NADH 100 μ g/ml+ 15 6.6 30 45.2 60 50.6 carnitine 1mg/mlNADH 200 μ g/ml+ 15 18.4 30 56.4 60 70.5 carnitine 2mg/ml
MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) test
MPTP as main on neural skeletal system level the purposes of activated neurotoxin can be the remarkable experimental model that is used to study parkinson and biochemistry and clinical onset mechanism.
In monkey and mice, the MPTP of high dose (40mg/kg) induced movement hypofunction and bradykinesia symptom, these are parkinsonian characteristics, follow the obvious minimizing of DOPA and metabolite thereof.Whether in these trials, studied behavior that mice brought out by MPTP and athletic injury and dopamine concentration can be changed and corrected by independent NADH or the administration of L-carnitine or this two kinds of combinations of substances administrations.
The C57 BE/6 system black Mus of body weight as 20g used in these tests; One group of mice in contrast, other groups subcutaneous injection twice 40mg/kg MPTP, 24 hours at interval.In MPTP injection three weeks of back, estimate the mobility who all treats animal and control animal.Three weeks are also carried out the mensuration of DOPA in MPTP treatment back.Setting in motion test immediately after both also having treated with carnitine with NADH; According to the described operation of Archer (Archer T., Fredrikson A., " psychopharmacology " 88,141,1986), use the lucite photographing unit that between differing heights, moves around by two kinds of infrared ray assessment mobilitys.
Mobility's minimizing of being brought out by MPTP confirms to surpass 80% in control mice, and independent NADH and L-carnitine have reduced by 60% and 70% mobility respectively, and the combination of these two kinds of materials makes the mobility almost return to normal level (reducing 20%).The DOPA concentration results that also interesting is in the stricture of vagina shape flesh has reduced 90%, but almost has been normal level in the treatment mice in the control mice of MPTP administration.Also have, in these trials, single effect with the L-carnitine is seemingly almost negligible, and single effect with NADH equals 40%, yet both combinations make DOPA return to very level near normal structure concentration.
Report that below some are according to compositions embodiment of the present invention: (1) L-endogenous toxin alkali 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
Pyridoxol mg 3
Selenium mg 20
Zinc 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
Acetone acid (piruvic 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.
CN99805644A 1998-04-17 1999-04-14 Composition comprising L-carnitine or an alkanoyl L-carnitine and NADH and/or NADPH Pending CN1299283A (en)

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CN104306390A (en) * 2014-10-23 2015-01-28 苏州人本药业有限公司 Application of reduced coenzyme II
WO2016131320A1 (en) * 2015-02-17 2016-08-25 苏州人本药业有限公司 Use of nadph in preparing medicines for treatment of heart diseases
CN109105702A (en) * 2018-08-30 2019-01-01 泓博元生命科技（深圳）有限公司 A kind of preparation method of composition containing NADH, application and energy extender
CN109170907A (en) * 2018-08-30 2019-01-11 泓博元生命科技（深圳）有限公司 A kind of preparation method of composition containing NMN, application and sports drink
CN109496154A (en) * 2017-12-22 2019-03-19 邦泰生物工程(深圳)有限公司 A kind of NADH compound and its preparation and application

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DE10326822A1 (en) * 2003-06-11 2005-01-05 Herzpharma Vita-Check Diagnosegeräte GmbH Dietary supplement, e.g. for increasing general performance, concentration and endurance, comprises NADH, L-carnitine, coenzyme Q10, L-carnosine, succinic acid, ascorbic acid and bioflavonoids
US20120214870A1 (en) * 2009-08-31 2012-08-23 University Of South Australia Methods for diagnosis and treatment of chronic fatigue syndrome
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CN101677912A (en) * 2007-05-11 2010-03-24 希格马托制药工业公司 Gel useful for the delivery of cosmetic active ingredients
CN104306390A (en) * 2014-10-23 2015-01-28 苏州人本药业有限公司 Application of reduced coenzyme II
WO2016062125A1 (en) * 2014-10-23 2016-04-28 苏州人本药业有限公司 Use of reduced coenzyme ii
WO2016131320A1 (en) * 2015-02-17 2016-08-25 苏州人本药业有限公司 Use of nadph in preparing medicines for treatment of heart diseases
CN109496154A (en) * 2017-12-22 2019-03-19 邦泰生物工程(深圳)有限公司 A kind of NADH compound and its preparation and application
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CN109170907A (en) * 2018-08-30 2019-01-11 泓博元生命科技（深圳）有限公司 A kind of preparation method of composition containing NMN, application and sports drink

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