WO2017107863A1 - 一种用于治疗运动神经元病的组合物及其用途 - Google Patents

一种用于治疗运动神经元病的组合物及其用途 Download PDF

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WO2017107863A1
WO2017107863A1 PCT/CN2016/110316 CN2016110316W WO2017107863A1 WO 2017107863 A1 WO2017107863 A1 WO 2017107863A1 CN 2016110316 W CN2016110316 W CN 2016110316W WO 2017107863 A1 WO2017107863 A1 WO 2017107863A1
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vitamin
injection
ornithine
acid
tyrosine
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PCT/CN2016/110316
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English (en)
French (fr)
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岳茂兴
黄彤舸
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岳茂兴
黄彤舸
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Priority claimed from CN201510969710.XA external-priority patent/CN107115332A/zh
Priority claimed from CN201611153606.4A external-priority patent/CN107184582A/zh
Application filed by 岳茂兴, 黄彤舸 filed Critical 岳茂兴
Priority to GB1809655.2A priority Critical patent/GB2561747B/en
Priority to EP16877674.8A priority patent/EP3395341A4/en
Priority to CH00785/18A priority patent/CH713469B1/de
Priority to ES201890043A priority patent/ES2699722B1/es
Priority to DE112016005857.8T priority patent/DE112016005857T5/de
Publication of WO2017107863A1 publication Critical patent/WO2017107863A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4415—Pyridoxine, i.e. Vitamin B6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate

Definitions

  • the invention belongs to the field of pharmacy and relates to a composition for treating motor neuron diseases and uses thereof.
  • Motor neuron disease is a group of chronic progressive degenerative diseases with selective etiology of spinal cord anterior horn cells, brainstem motor neurons, cortical vertebral cells and vertebral body bundles. It is characterized by degeneration, necrosis and apoptosis of progressive upper and lower motor neurons. Clinically, there are both upper and/or lower motor neuron impaired performance, which are different combinations of muscle weakness, muscle atrophy and vertebral body sign. Ultimately, respiratory failure is often caused by death, and sensation and sphincter function are generally unaffected.
  • ALS amyotrophic lateral sclerosis
  • SMA spinal muscular atrophy
  • PBP progressive bulbar palsy
  • ALS is the most common type of chronic motor neuron disease, commonly known as “gradual freezing human disease.”
  • the main symptomatic medications are: Lirutai (also known as riluzole), the only drug approved by the US Food and Drug Administration (FDA) for the treatment of ALS, a drug that is resistant to glutamate. It is also the only drug that proves to be effective and clinically effective for animal models, which can delay the progression of the disease and only extend the survival of patients for about half a year.
  • Other medications include: mecobate, vitamin B, vitamin E And various neurotrophic drugs.
  • Chinese medicine belongs to the "sickness syndrome", the pathogenesis is the five internal organs, the deficiency of Jingjin, the deficiency of Qi and blood, the dystrophy of muscle tendons, and the deficiency of spleen and stomach.
  • the pathogenesis is the five internal organs, the deficiency of Jingjin, the deficiency of Qi and blood, the dystrophy of muscle tendons, and the deficiency of spleen and stomach.
  • acupuncture and medicine pay attention to the conditioning of spleen and stomach function, spleen and tonic, tonic heart, lung, liver, kidney and four organs. The patient's symptoms are improved, the disease progression is delayed, and the motor neuron pain is alleviated.
  • Another object of the invention is to provide the use of the above composition.
  • Still another object of the present invention is to provide a method of treating motor neuron disease using the above composition.
  • composition for treating a motor neuron disease comprising the following ratios of substances per unit of the composition:
  • the L-ornithine is 0.325-8 g or the L-ornithine salt having an L-ornithine content of 0.325-8 g, the aspartic acid 0.625-5 g, and the vitamin B 6 3-20 g;
  • L-ornithine is 0.325 to 0.65 g or L-ornithine having an L-ornithine content of 0.325 to 0.65 g, aspartic acid 0.625 to 1.25 g, and vitamin B 6 3 to 10 g.
  • each of the compositions further comprises any one or more of the following: arginine, isoleucine, leucine, lysine, methionine, phenylalanine, Threonine, tryptophan, valine, histidine, glycine, alanine, valine, asparagine, cysteine, glutamic acid, serine, tyrosine, vitamin B 1 , vitamin B 2 , vitamin B 3 , pantothenic acid, biotin, folic acid, vitamin B 12 , vitamin C, KCl;
  • amino acids may be replaced by various soluble salts of amino acids or derivatives thereof.
  • lysine is replaced by lysine acetate
  • cysteine is replaced by N-acetyl-L-cysteine
  • tyrosine is replaced by N-acetyl-L-tyrosine
  • the ratio of the amount of each amino acid is: arginine 2.0 to 10 g, isoleucine 2.0 to 10 g, leucine 3.0 to 15 g, equivalent to lysine acetate having a lysine content of 1.5 to 10 g, methionine 0.2 to 3 g, phenylalanine 0.3 to 3 g, threonine 1.0 to 10 g, tryptophan 0.3 to 3 g, proline 2.5 to 15 g, histidine 1.0 to 8 g, glycine 1.5 to 8 g, and alanine 2.0 to 10g, proline 1.5 ⁇ 8g, asparagine 0.1 ⁇ 3g, corresponding to cysteine content of 0.1 ⁇ 3g N-acetyl-L-cysteine, glutamic acid 1.0 ⁇ 10g, serine 0.5 ⁇ 5g , corresponding to N-acetyl-L-tyrosine having a tyrosine content of 0.1 to 3 g;
  • the proportion of vitamins is: vitamin B 1 1.0 ⁇ 4.0mg, vitamin B 2 1.0 ⁇ 4.0mg, vitamin B 3 10 ⁇ 40mg, pantothenic acid 3.0 ⁇ 10mg, biotin 0.1 ⁇ 0.4mg, folic acid 0.1 ⁇ 0.8mg, vitamins B 12 2.0 ⁇ 12 ⁇ g; vitamin C 1.0-6.0g;
  • the amount of KCl is 10% KCl 5-10 ml;
  • the ratio of the amount of each amino acid is: lysine 2.2 ⁇ 4.4g, isoleucine 2.2 ⁇ 4.4g, leucine 3.4 ⁇ 6.8g, lysine vinegar with lysine content of 1.8775 ⁇ 3.755g Acid salt, methionine 0.3-0.6g, phenylalanine 0.4-0.8g, threonine 1.15-2.3g, tryptophan 0.375-0.75g, proline 2.65-5.3g, histidine 1.175 ⁇ 2.35g, Glycine 1.575 ⁇ 3.15g, alanine 2.075 ⁇ 4.15g, proline 1.775 ⁇ 3.55g, asparagine 0.1375 ⁇ 0.275g, corresponding to N-acetyl-L-half with cysteine content 0.15 ⁇ 0.3g Cystine, glutamic acid 1.425 ⁇ 2.85g, serine 0.925 ⁇ 1.85g, corresponding to tyrosine content 0.175 ⁇ 0.35g N-acetyl-L-tyrosine
  • the proportion of vitamins is: vitamin B 1 1.0 ⁇ 4.0mg, vitamin B 2 1.0 ⁇ 4.0mg, vitamin B 3 10 ⁇ 40mg, pantothenic acid 3.0 ⁇ 10mg, biotin 0.1 ⁇ 0.4mg, folic acid 0.1 ⁇ 0.8mg, vitamins B 12 2.0 ⁇ 12 ⁇ g; vitamin C 1.0-6.0g;
  • the amount of KCl is 10% KCl 5-10 ml;
  • the ratio of the ratio of each amino acid is: arginine 3.0-10g, isoleucine 3.0-10g, leucine 5.0-15g, lysine acetate equivalent to lysine content 3.0-10g, methionine 0.5 ⁇ 3g, phenylalanine 0.5 ⁇ 3g, threonine 3.0 ⁇ 10g, tryptophan 0.5 ⁇ 3.0g, proline 5.0 ⁇ 15g, histidine 3.0 ⁇ 8.0g, glycine 3.0 ⁇ 8.0g, alanine 3.0 to 10 g of acid, 3.0 to 8.0 g of proline, 0.1 to 3.0 g of asparagine, N-acetyl-L-cysteine having a cysteine content of 0.1 to 3.0 g, and glutamic acid 3.0 to 10 g, 0.5 to 5.0 g of serine, corresponding to N-acetyl-L-tyrosine having a tyrosine content of 0.1 to 3 g;
  • the proportion of vitamins is: vitamin B 1 2.0 ⁇ 4.0mg, vitamin B 2 2.0 ⁇ 4.0mg, vitamin B 3 20 ⁇ 40mg, pantothenic acid 6.0 ⁇ 10mg, biotin 0.2 ⁇ 0.4mg, folic acid 0.2 ⁇ 0.8mg, vitamins B 12 4.0 to 12 ⁇ g; vitamin C 2.0-6.0 g.
  • the composition contains a substance in a ratio of the following amounts per unit of the composition:
  • Isoleucine 4.4g leucine 6.8g, lysine acetate 5.3g (corresponding to lysine 3.775g), methionine 0.6g, phenylalanine 0.8g, threonine 2.3g, color ammonia Acid 0.75g, valine 5.3g, arginine 4.4g, histidine 2.35g, glycine 3.15g, alanine 4.15g, valine 3.55g, aspartic acid 1.25g, asparagine 0.275g , N-acetyl-L-cysteine 0.4g (corresponding to cysteine 0.3g), glutamic acid 0 or 2.85g, L-ornithine hydrochloride 0.83g (equivalent to L-ornithine) 0.65g), serine 1.85g, N-acetyl-L-tyrosine 0.43g (corresponding to tyrosine 0.35g), vitamin B 6 3.0 ⁇ 10g, 10% KCl 0 or 5-10ml
  • compositions may also contain an appropriate amount of 5% dextrose sodium chloride injection (5% GNS) or 0.9% sodium chloride injection (0.9% NS) or 10% glucose injection.
  • Insulin may also be added to the composition containing glucose in an amount of insulin per unit (1 u) of insulin to 3 to 5 g of glucose, preferably each unit (1 u) of insulin to 4 g of glucose.
  • the specific formulation of the composition is:
  • the above compound amino acid injection contains: 8.80 g of isoleucine, 13.60 g of leucine, 10.60 g of lysine acetate (corresponding to 7.51 g of lysine), and 1.20 g of methionine, phenylalanine per 1000 ml.
  • the dosage form of any of the above compositions is any dosage form permitted by pharmaceutically acceptable dosage forms or health care products; the dosage form of the composition is preferably an injection, an oral solution, a tablet, a granule, a capsule, or a granule.
  • the corresponding dosage form may contain conventional excipients suitable for such dosage forms, such as water, magnesium stearate, dextrin, and the like, all of which are well known to those skilled in the art.
  • compositions for the preparation of a medicament or health care product for treating motor neuron disease.
  • the motor neuron disease includes amyotrophic lateral sclerosis, spinal muscular atrophy, primary lateral sclerosis, progressive bulbar palsy, preferably amyotrophic lateral sclerosis.
  • a method for treating a motor neuron disease which method is administered to a patient by injection or orally; the injection method is preferably intravenous.
  • Each of the treatments in the method is administered to the patient by injection or oral administration for 10-40 days, preferably 15-30 days; after the end of one treatment period, the appropriate time (for example, 10-15 days) can be taken according to the treatment needs. ) Continue to the next course of treatment or not to take the next course of treatment.
  • glucose injection and insulin can be supplemented for patients who have difficulty swallowing, coughing, or eating difficulties.
  • the daily dose of vitamin B 6 is less than 1.0 g, and the therapeutic effect is not obvious.
  • the direct intravenous infusion of the diluted vitamin B 6 treatment effect is not obvious.
  • the content of each substance in the unit composition of the present invention can also be expressed in terms of parts by mass, etc., without affecting the proportional relationship of the contents of the substances in the composition.
  • the unit per unit generally refers to the dose used by the patient in one day, and can be appropriately adjusted according to the condition.
  • the daily use dose can be made into a package such as a bottle or a bag of injection, or a plurality of basic units such as tablets can be made according to the use, and the like.
  • each amino acid is preferably an L-form amino acid.
  • the resting potential refers to a potential difference between the inside and outside of the cell membrane when the cells are not stimulated (at rest). It is well known that resting potentials are present in nerve and muscle fibers. In 1902, J. Bernstein first proposed that the K + distribution on both sides of the nerve cell membrane is not equal and that the membrane permeability to potassium is the cause of resting potential. Resting K + neurons of the high permeability of Na + is low, it is this selectively permeable membrane formed inside and outside the K + concentration gradient is generated transmembrane potential difference. It can be seen that the uneven distribution of ions inside and outside the cell membrane and the permeability to different ions in a quiet state are prerequisites for the generation of resting potential.
  • the extracellular Na + concentration is higher than that in the cells, and the intracellular K + concentration is much higher than the extracellular, so there is a difference in ion concentration on both sides of the cell membrane; in addition, there is a potential difference.
  • the ion diffusion depends on the power density difference and the potential difference between the cells in a quiet state, but there is permeability of K +, Na + and permeability to other small ions.
  • K + diffusion to the outside of the membrane at a power density difference because K + is a positive ion, negative outer outdiffusion formed positive potential difference will further prevent diffusion of K +, K + concentration when differential force causes outflow and
  • the outflow of K + is stopped, and the transmembrane potential at this time is called the K + equilibrium potential.
  • the main factors affecting the resting potential level are: 1 extracellular K + concentration can affect the size of resting potential, such as increased extracellular K + concentration, decreased intracellular K + concentration, decreased K + outflow, resting The potential is reduced; 2 the relative permeability of the membrane to K + and Na + can affect the magnitude of the resting potential. If the permeability of the membrane to K + increases, the resting potential increases, such as the membrane to Na + As the permeability increases, the resting potential will decrease; 3 the level of sodium pump activity has an effect on the resting potential.
  • the action potential refers to a rapidly expandable potential change that occurs on the basis of the resting potential when the excitable cells are stimulated.
  • the mechanism of action potential generation is: the concentration of extracellular Na + is higher than that in the cell, and the Na + has a tendency of inflow under the difference of concentration.
  • the permeability to Na + is small, Na + inflow The amount is very small.
  • the cells are stimulated, a small amount of Na + channels on the cell membrane are activated and opened, and Na + flows inward with the difference in concentration and potential difference.
  • the negative potential value in the membrane gradually becomes smaller, depolarization occurs, and when depolarization reaches a certain level
  • the critical membrane potential that causes the membrane to suddenly increase Na + permeability is called the threshold potential.
  • the threshold potential is about 10-20 mv smaller than the resting potential, and the threshold potential of the nerve cells is about -55 mv.
  • the stimulus must be such that when the negative potential value in the membrane is reduced to the threshold potential, the action potential can be erupted.
  • Na + Since Na + is diffused along the concentration difference and the potential difference, the Na + inflow velocity is fast, the negative potential value in the film rapidly becomes small, disappears, and further turns into a positive potential, and the positive potential formed in the film is opposite to Na + when an electric field is formed in the flow resistance, to prevent the flow of Na +, Na + causes the power flow (density difference) of the power flow (electric resistance) is equal to the blocking Na +, Na + influx is stopped, then the maximum action potential
  • the amplitude which is the electro-chemical equilibrium potential of Na + , forms the rising branch of the action potential.
  • the sodium channel has a short open time and is quickly inactivated and closed.
  • the permeability of the cell membrane to K + is increased, and a large amount of K +
  • the concentration difference and the potential difference rapidly flow out, so that the potential inside the film changes from a positive value to a negative value, repolarization occurs, and the resting state is restored to form a falling branch of the action potential.
  • the rising branch of the action potential is the electro-chemical equilibrium potential formed by the Na + inflow
  • the falling branch of the action potential is the electro-chemical equilibrium potential formed by the K + outflow.
  • the membrane potential is basically restored to the resting state, but the ion distribution is not restored, there is excessive K + outside the cell, and there is too much Na + in the cell, which activates the sodium pump on the cell membrane.
  • extracellular K + is pumped into the cells, and too much Na + in the cells is pumped out of the cells to restore the original resting state level, ready for the next excitement.
  • Amino acid is the most basic substance that constitutes a biological protein and is related to life activities. It is the basic unit that constitutes a protein molecule in a living organism and has a close relationship with the life activities of living things. It has special physiological functions in antibodies and is one of the indispensable nutrients in the body. It can exert the following effects through metabolism in the human body: 1 synthesis of proteins and nucleic acids; 2 conversion into nitrogenous substances such as acids, hormones, antibodies, creatine; 3 conversion to carbohydrates and fats; 4 oxidation to carbon dioxide and water and urea ,generate energy.
  • L-ornithine is a non-protein amino acid that is mainly involved in the urea cycle in the organism and plays an important role in the discharge of ammonia nitrogen in the body.
  • carbamyl phosphate synthase I is an enzyme in the urea cycle, which is present in the mitochondria, with ammonia as the nitrogen source, requires N-acetylglutamate, and the resulting carbamoyl phosphate is used to synthesize urea;
  • ammonia Formyl phosphate synthase II is present in the cytosol, using glutamine as a nitrogen source, does not require N-acetylglutamate, and synthetic carbamoyl phosphate is used to synthesize pyrimidine.
  • the first step catalyzed by carbamyl phosphate synthase I is the rate limiting step of the urea cycle.
  • Carbamoyl phosphate synthase I is activated by an N-acetylglutamate allosteric enzyme. This metabolite is synthesized by glutamate and acetyl CoA catalyzed by N-acetylglutamate synthetase.
  • the rate of amino acid degradation increases, the concentration of glutamic acid increases as a result of transamination, and the increase in glutamate concentration promotes the synthesis of N-acetylglutamate, resulting in the activation of carbamyl phosphate synthase.
  • excess nitrogen produced by amino acid degradation is effectively excreted from the body. Since arginine is an activator of N-acetylglutamate synthetase, the increase in arginine concentration also accelerates the synthesis of urea.
  • Aspartic acid promotes the tricarboxylic acid cycle by deamination to oxaloacetate, and aspartic acid is an important component in the tricarboxylic acid cycle. And aspartic acid plays an important role in the ornithine cycle and nucleotide synthesis, and is a synthetic precursor of various amino acids and purine and pyrimidine bases. It has strong affinity for cells and can be used as a carrier of potassium and magnesium ions to transport electrolytes to the myocardium, promote cell depolarization, maintain myocardial contractility, and reduce myocardial oxygen consumption. When coronary circulatory disorders cause hypoxia, Myocardium has a protective effect.
  • aspartic acid can directly participate in the urea cycle and participate in the tricarboxylic acid cycle and the synthesis of nucleic acids in hepatocytes, which is beneficial to repair damaged liver cells.
  • aspartic acid promotes the energy production of hepatocytes due to the indirect promotion of the metabolism of tricarboxylic acid in hepatocytes, and promotes the energy production of hepatocytes. restore.
  • So L-ornithine and Aspartic acid can stimulate liver urea cycle activity and promote glutamine synthesis, greatly enhance liver detoxification function, rapidly reduce blood ammonia, and promote liver cell repair and regeneration. Therefore, the presence of amino acids in the human body not only provides an important raw material for the synthesis of proteins, but also provides a material basis for promoting growth, normal metabolism, and life.
  • Vitamin B vitamins are water-soluble vitamins, including vitamin B 1 , vitamin B 2 , vitamin B 6 , vitamin B 12 , niacin, pantothenic acid, folic acid, etc., which promote metabolism in the body and convert sugar, fat, protein, etc. into heat. Missing substance. They have a synergistic effect that regulates metabolism and enhances the immune system's ability to promote cell growth and division. Vitamin B 6 may be the most important of all vitamin B families. Vitamin B 6 is also known as pyridoxine, which includes three compounds, pyridoxine, pyridoxal and pyridoxamine.
  • pyridoxal and pyridoxamine In animal tissues may be converted to pyridoxine or pyridoxal pyridoxamine, vitamin B 6 and there is more animal tissue to pyridoxal and pyridoxamine form.
  • Pyridoxal and pyridoxamine, pyridoxal phosphate and pyridoxine phosphate can be mutually transformed, and finally exist in the form of pyridoxal phosphate and pyridoxine phosphate which are more active, and participate in transamination.
  • the muscles of the human body contain 70% to 80% of vitamin B 6 in the whole body. Vitamin B 6 plays a key role in the metabolism of proteins, lipids and carbohydrates. Therefore, a large number of people who suffer from vitamin B 6 may have disorders including amino acid metabolism.
  • Vitamin B 6 is an important coenzyme for the metabolism and synthesis of amino acids, and participates in the physiological processes such as the metabolism of unsaturated fatty acids. It is a coenzyme of many important enzyme systems in the body and is a necessary nutrient for the normal development of animals, bacteria and yeast. In addition, vitamin B 6 is also a natural diuretic, diuretic can detoxification, intravenous vitamin B 6 5g, about 385ml of urine. Vitamin B 6 is a coenzyme of human amino acid metabolism, neurotransmitter ⁇ -aminobutyric acid (GABA) and glutamic acid (Glu). It is known that more than 60 kinds of enzymes in the liver require vitamin B 6 to participate in the promotion of normal enzyme metabolism in the body. The aspect plays a very important role, and the half-life of vitamin B 6 in the body is short and it is quickly excreted. And pyridoxal phosphate also has a special function that promotes the rate at which amino acids and potassium enter cells.
  • Potassium is one of the most important inorganic cations in the body. It is second only to sodium in the body electrolyte, 98% of which is present in cells, only 2% in extracellular fluid, and serum potassium concentration is 3.5-5.5mmol/ L. The difference in the concentration of potassium inside and outside the cell is maintained by the energy translocation of the cell membrane Na + -K + -ATPase. Potassium is an important material basis for the function of all organs in the body and participates in all organs of the body.
  • Acetylcholine is an excitatory neurotransmitter on the vertebrate neuromuscular junction (motor endplate).
  • Acetylcholine is synthesized in the axonal distal axoplasm of cholinergic neurons.
  • Choline and acetyl-CoA form acetylcholine under the action of choline acetyltransferase.
  • Nerve cells cannot synthesize choline, which is mainly supplied by blood circulation, and is taken into cells by a specific carrier on the cell membrane, the choline transporter.
  • Cholinesters synthesized in the liver, choline stored in glial cells, and choline produced by hydrolysis of acetylcholine released from nerve endings can also be a source of choline in acetylcholine synthesis.
  • the arrival of the action potential stimulates the presynaptic membrane to greatly increase the permeability to Ca 2+ , and Ca 2+ flows into the axon along its ion concentration gradient.
  • Acetylcholine is followed by a phenomenon in the synaptic cleft called acetylcholinesterase that rapidly degrades to acetic acid and choline, while the postsynaptic membrane rapidly returns to resting potential. And in this process, the action of acetylcholine increases the permeability of the membrane to Na + and K + . Since the electrochemical gradient of the postsynaptic membrane is larger than K + , the inward flow of Na + results in depolarization, causing the transmembrane potential to collapse.
  • the resting potential, action potential, generator potential and synaptic potential generated by general neurons all depend on the ion gradient formed by the active transport of the blood-brain barrier, and the transmission and accurate reproduction of nerve impulses also depend on the blood-brain barrier on neurons and The shielding effect of nerve fibers.
  • glutamate levels in the cerebrospinal fluid of patients with motor neuron disease are three times higher than those in the 80% control group.
  • excessive extracellular glutamate concentration will over-stimulate its receptor and produce significant toxic effects on the central nervous system.
  • the glutamate level in the cerebrospinal fluid of some patients was significantly decreased, the motor neurons were repaired, and the symptoms of the patients were significantly improved.
  • glutamic acid in the body and cysteine and glycine in the present invention can produce glutathione, scavenge free radicals in the body, and alleviate motor neuron diseases. The symptoms of the patient.
  • glutamate dehydrogenase coenzyme is NAD + or NADP +
  • excess ammonia can be combined with the valley.
  • Combination of glutamic acid to produce glutamine, glutamine and aspartic acid in the present invention to synthesize pyrimidine nucleotides under the action of aminomethyl acyl phosphate synthase II, and glutamine can also be used in the present invention as well as glycine and Aspartic acid synthesizes purine nucleotides, and in the liver cytosol, glutamate and the glycine and aspartic acid in the present invention are involved in the de novo synthesis of purine nucleotides, providing a source of nucleotides in vivo.
  • the synthesis of pyrimidine nucleotides and purine nucleotides promotes protein synthesis, repairs damaged neuronal cells, and excess ammonia produced by oxidative deamination of glutamate is excreted by L-ornithine-activated intrahepatic urea cycle. 3
  • the produced glutamine can directly decompose into ammonia and glutamate through the blood-brain barrier. Although the extracellular glutamate concentration has obvious toxic effects on the central nervous system, intracellular glutamate is breast-feeding.
  • Vitamin B 6 is not only a natural diuretic, diuretic can detoxify, and pyridoxal phosphate can promote the rate of amino acid and potassium entering cells.
  • a large dose of vitamin B 6 promotes the entry of amino acids into neuronal cells.
  • the rate which provides the raw materials and energy for the repair of neurons, accelerates the repair of damaged neuronal cells.
  • K + rapid entry into neuronal cells promotes the metabolism of intracellular sugars and proteins, regulates intracellular osmotic pressure and acid-base balance, increases cell membrane resting potential, increases neuromuscular excitability, and normal myocardial contraction Get coordinated.
  • the present invention since the present invention contains various amino acids, it can provide fresh nutrition to the blood, promotes regeneration of damaged nerve cells, improves metabolic microenvironment, and enhances neuronal survival through amino acid metabolism and blood circulation. Capability, the present invention provides a substrate for metabolism and strong kinetic energy, which alleviates the patient's condition and even reverses the condition. And ornithine and aspartic acid can stimulate liver urea cycle activity, and a large amount of ammonia produced during amino acid metabolism can be excreted through the urea cycle. Whether in the body, whether it is neuromodulation or hormonal regulation, it ultimately works through enzymes.
  • the large dose of vitamin B 6 added in the present invention provides sufficient coenzyme for human amino acid metabolism, neurotransmitters ⁇ -aminobutyric acid (GABA) and glutamic acid (Glu).
  • GABA ⁇ -aminobutyric acid
  • Glu glutamic acid
  • the human body can transport ammonia from the brain, muscles and other tissues to the liver or kidney through glutamine.
  • Glutamine is not toxic, and it is a way for the human body to quickly relieve ammonia toxicity. In this disease, it also rapidly relieves the extratoxicity of extracellular extra-high glutamate concentration on the central nervous system, while storing and transporting ammonia.
  • glutamine When transported to the liver, glutamine releases ammonia to synthesize urea; when transported to the kidney, glutamine releases ammonia directly out of the urine; it can be used to synthesize amino acids, purines, pyrimidines, etc. in various tissues. Nitrogen-containing substances. That is to say, the invention can promote the synthesis of glutamine, relieve the obvious toxic effect of extracellular extra-high glutamic acid concentration on the central nervous system, and glutamine can directly pass the blood-brain barrier for the repair of brain nerve cells. Partial amino acids, purines and pyrimidines are provided. 2 The synthesis of glutathione can effectively remove free radicals in the body and alleviate the symptoms of patients with motor neuron disease.
  • the amino acids in the present invention also provide energy and raw materials for the neurotrophic factor to repair damaged nerve cells.
  • L-ornithine acts as a reaction substrate for the urea cycle due to the presence of L-ornithine, rapidly activating the urea cycle in the liver cells, and generating harmful ammonia from the body. Exclusion of the body by urea ensures normal metabolism of the body.
  • the present invention contains aspartic acid, it is a synthetic precursor of various amino acids and purine and pyrimidine bases, and it has strong affinity for cells, and can be used as a carrier of potassium and magnesium ions to transport electrolytes to the myocardium and promote cells.
  • Polarization maintaining myocardial contractility. It not only provides energy and raw materials for neurotrophic factors, repairs damaged nerve cells, but also promotes K + into neuronal cells and maintains myocardial contractility. And combined with L-ornithine, it can stimulate liver urea circulation activity to greatly enhance liver detoxification function, rapidly reduce blood ammonia, promote the repair and regeneration of liver cells themselves, thereby enhancing the body's own immunity, and essentially treating motor nerves.
  • the first disease, and the invention has no toxic side effects and low treatment cost, and is the drug of choice for patients with motor neuron disease.
  • the composition provided by the invention can alleviate or even reverse the pathogenesis of motor neuron disease, basically can improve the clinical symptoms of patients with motor neuron disease, and even can live normally, has a better therapeutic effect, and the raw materials of the composition feed.
  • Source materials, long-term use has no toxic side effects, low cost of treatment, there is basically no economic burden for patients with motor neuron disease, suitable for clinical promotion.
  • Figure 1 is a case 1 EMG report.
  • Figure 2 shows the diagnosis of ALS diagnosed in Case 3 at Peking University Third Hospital.
  • Figure 3 is a case 4 EMG report.
  • Figure 4 is a case 5 EMG report.
  • a pharmaceutical composition comprising L-ornithine hydrochloride equivalent to L-ornithine 2.5 g of about 3.19 g, aspartic acid 1.5 g and vitamin B 6 10 g, added to 5% glucose and sodium chloride injection It can be used in 250ml.
  • a pharmaceutical composition comprising L-ornithine hydrochloride 0.415 g (corresponding to L-ornithine 0.325 g), aspartic acid 0.625 g and vitamin B 6 3.0 g, added to 5% glucose sodium chloride
  • the injection can be used in 250ml.
  • a pharmaceutical composition comprising 0.83 g of L-ornithine hydrochloride (corresponding to 0.65 g of L-ornithine), 1.25 g of aspartic acid, 5.0 g of vitamin B 6 , and added to 0.9% sodium chloride injection In 250 ml of liquid.
  • a pharmaceutical composition comprising a compound amino acid injection 250ml [containing isoleucine 2.2g, leucine 3.4g, lysine acetate 2.65g (corresponding to lysine 1.8775g), styrene-acrylic acid 0.4 g, threonine 1.15 g, tryptophan 0.375 g, arginine 2.2 g, histidine 1.175 g, glycine 1.575 g, alanine 2.075 g, proline 1.775 g, aspartic acid 0.625 g, asparagine 0.1375g, N-acetyl-L-cysteine 0.2g (corresponding to cysteine 0.15g), L-ornithine hydrochloride 0.415g (equivalent to L-ornithine 0.325) g) 0.925 g of serine, 0.215 g of N-acetyl-L-tyrosine (corresponding to 0.175 g of tyrosine), and
  • a pharmaceutical composition comprising a compound amino acid injection 250ml [containing isoleucine 2.2g, leucine 3.4g, lysine acetate 2.65g (corresponding to lysine 1.8775g), methionine 0.3 g, phenylalanine 0.4g, threonine 1.15g, tryptophan 0.375g, proline 2.65g, arginine 2.2g, histidine 1.175g, glycine 1.575g, alanine 2.075g, ⁇ 1.775g, aspartate 0.625g, asparagine 0.1375g, N-acetyl-L-cysteine 0.2g (equivalent to cysteine 0.15g), glutamic acid 1.425g, L-bird Acid hydrochloride 0.415g (corresponding to L-ornithine 0.325g), serine 0.925g, N-acetyl-L-tyrosine 0.215g (corresponding to tyrosine 0.175g)], and vitamin
  • a pharmaceutical composition comprising a compound amino acid injection 250ml [containing isoleucine 2.2g, leucine 3.4g, lysine acetate 2.65g (corresponding to lysine 1.8775g), methionine 0.3 g, phenylalanine 0.4g, threonine 1.15g, tryptophan 0.375g, proline 2.65g, arginine 2.2g, histidine 1.175g, glycine 1.575g, alanine 2.075g, ⁇ 1.775g, aspartate 0.625g, asparagine 0.1375g, N-acetyl-L-cysteine 0.2g (equivalent to cysteine 0.15g), glutamic acid 1.425g, L-bird Acid hydrochloride 0.415g (corresponding to L-ornithine 0.325g), serine 0.925g, N-acetyl-L-tyrosine 0.215g (corresponding to tyrosine 0.175g)], and vitamin
  • a pharmaceutical composition comprising a compound amino acid injection 250ml [containing isoleucine 2.2g, leucine 3.4g, lysine acetate 2.65g (corresponding to lysine 1.8775g), methionine 0.3 g, phenylalanine 0.4g, threonine 1.15g, tryptophan 0.375g, proline 2.65g, arginine 2.2g, histidine 1.175g, glycine 1.575g, alanine 2.075g, ⁇ 1.775g, aspartate 0.625g, asparagine 0.1375g, N-acetyl-L-cysteine 0.2g (equivalent to cysteine 0.15g), glutamic acid 1.425g, L-bird Acid hydrochloride 0.415g (corresponding to L-ornithine 0.325g), serine 0.925g, N-acetyl-L-tyrosine 0.215g (corresponding to tyrosine 0.175g)], and vitamin
  • a pharmaceutical composition comprising a compound amino acid injection 250ml [containing isoleucine 2.2g, leucine 3.4g, lysine acetate 2.65g (corresponding to lysine 1.8775g), methionine 0.3 g, phenylalanine 0.4g, threonine 1.15g, tryptophan 0.375g, proline 2.65g, arginine 2.2g, histidine 1.175g, glycine 1.575g, alanine 2.075g, ⁇ 1.775g, aspartate 0.625g, asparagine 0.1375g, N-acetyl-L-cysteine 0.2g (equivalent to cysteine 0.15g), glutamic acid 1.425g, L-bird Acid hydrochloride 0.415g (corresponding to L-ornithine 0.325g), serine 0.925g, N-acetyl-L-tyrosine 0.215g (corresponding to tyrosine 0.175g)], and vitamin
  • a pharmaceutical composition comprising a compound amino acid injection 250ml [containing isoleucine 2.2g, leucine 3.4g, lysine acetate 2.65g (corresponding to lysine 1.8775g), methionine 0.3 g, phenylalanine 0.4g, threonine 1.15g, tryptophan 0.375g, proline 2.65g, arginine 2.2g, histidine 1.175g, glycine 1.575g, alanine 2.075g, ⁇ 1.775g, aspartate 0.625g, asparagine 0.1375g, N-acetyl-L-cysteine 0.2g (equivalent to cysteine 0.15g), glutamic acid 1.425g, L-bird Acid hydrochloride 0.415g (corresponding to L-ornithine 0.325g), serine 0.925g, N-acetyl-L-tyrosine 0.215g (corresponding to tyrosine 0.175g)], and vitamin
  • a pharmaceutical composition comprising 500ml of compound amino acid injection [containing isoleucine 4.4g, leucine 6.8g, lysine acetate 5.3g (corresponding to lysine 3.775g), methionine 0.6 g, phenylalanine 0.8g, threonine 2.3g, tryptophan 0.75g, valine 5.3g, arginine 4.4g, histidine 2.35g, glycine 3.15g, alanine 4.15g, ⁇ 3.55g of amino acid, 1.25g of aspartic acid, 0.275g of asparagine, 0.4g of N-acetyl-L-cysteine (corresponding to 0.3g of cysteine), 2.85g of glutamic acid, L-bird Lysine hydrochloride 0.83g (equivalent to L-ornithine 0.65g), serine 1.85g, N-acetyl-L-tyrosine 0.43g (corresponding to tyrosine 0.35g)],
  • a pharmaceutical composition comprising 500ml of compound amino acid injection [containing isoleucine 4.4g, leucine 6.8g, lysine acetate 5.3g (corresponding to lysine 3.775g), methionine 0.6 g, phenylalanine 0.8g, threonine 2.3g, tryptophan 0.75g, valine 5.3g, arginine 4.4g, histidine 2.35g, glycine 3.15g, alanine 4.15g, ⁇ 3.55g of amino acid, 1.25g of aspartic acid, 0.275g of asparagine, 0.4g of N-acetyl-L-cysteine (corresponding to 0.3g of cysteine), 2.85g of glutamic acid, L-bird acid hydrochloride 0.83 g of (corresponding to L- ornithine 0.65g), serine 1.85g, N- acetyl -L- tyrosine 0.43 g of (corresponding to tyrosine 0.35
  • a pharmaceutical composition comprising 500ml of compound amino acid injection [containing isoleucine 4.4g, leucine 6.8g, lysine acetate 5.3g (corresponding to lysine 3.775g), methionine 0.6 g, phenylalanine 0.8g, threonine 2.3g, tryptophan 0.75g, valine 5.3g, arginine 4.4g, histidine 2.35g, glycine 3.15g, alanine 4.15g, ⁇ 3.55g of amino acid, 1.25g of aspartic acid, 0.275g of asparagine, 0.4g of N-acetyl-L-cysteine (corresponding to 0.3g of cysteine), 2.85g of glutamic acid, L-bird Lysine hydrochloride 0.83g (equivalent to L-ornithine 0.65g), serine 1.85g, N-acetyl-L-tyrosine 0.43g (corresponding to tyrosine 0.35g)],
  • a pharmaceutical composition comprising 1000ml of a compound amino acid injection (containing: L-ornithine hydrochloride equivalent to 3.5 g of L-ornithine, 2.50 g of aspartic acid, 8.80 g of arginine, Isoleucine 8.80g, leucine 13.60g, equivalent to lysine 7.51g of lysine acetate, methionine 1.20g, phenylalanine 1.60g, threonine 4.60g, tryptophan 1.50g , valine 10.60g, histidine 4.70g, glycine 6.30g, alanine 8.30g, proline 7.10g, asparagine 0.55g, equivalent to cysteine 0.60g N-acetyl-L- Cysteine, glutamic acid 5.70g, serine 3.70g, equivalent to 0.70g of tyrosine N-acetyl-L-tyrosine), and vitamin B 6 8.0g and vitamin C 3.0g, vitamins added to
  • a pharmaceutical composition comprising 1000ml of a compound amino acid injection (containing: L-ornithine hydrochloride equivalent to 4.5 g of L-ornithine, 2.80 g of aspartic acid, 8.30 g of arginine, Isoleucine 6.50g, leucine 12.00g, equivalent to lysine 7.51g of lysine acetate, methionine 1.60g, phenylalanine 1.40g, tryptophan 1.80g, valine 10.60g , histidine 4.80g, glycine 6.20g, alanine 8.50g, proline 7.10g, asparagine 0.55g, glutamic acid 5.70g, serine 3.70g, equivalent to 0.70g of tyrosine N-acetyl -L-tyrosine), and vitamin B 6 10g, vitamin B 1 3mg, vitamin B 2 3mg, vitamin B 3 40mg, pantothenic acid 8mg, biotin 0.4mg, foli
  • the vitamin may be directly added to the compound amino acid injection, or may be added to 5% glucose sodium chloride injection or 0.9% sodium chloride injection 250 ml.
  • a pharmaceutical composition comprising a compound amino acid injection of 1000 ml (containing: isoleucine 8.80 g, leucine 13.60 g, lysine acetate 10.60 g (corresponding to lysine 7.51 g), methionine 1.20g, 1.60g of phenylalanine, 4.60g of threonine, 1.50g of tryptophan, 10.60g of valine, 8.80g of arginine, 4.70g of histidine, 6.30g of glycine, 8.30g of alanine, Proline 7.10g, aspartic acid 2.50g, asparagine 0.55g, N-acetyl-L-cysteine 0.80g (corresponding to cysteine 0.60g), glutamic acid 5.70g, L- Ornithine hydrochloride 1.66 g (corresponding to L-ornithine 1.30 g), serine 3.70 g, N-acetyl-L-tyrosine 0.86 g (corresponding to
  • the vitamin may be directly added to the compound amino acid injection, or may be added to 250 ml of 5% glucose and sodium chloride injection or 250 ml of 0.9% sodium chloride injection.
  • a pharmaceutical composition comprising a compound amino acid injection of 1000 ml (containing: isoleucine 8.80 g, leucine 13.60 g, lysine acetate 10.60 g (corresponding to lysine 7.51 g), methionine 1.20g, 1.60g of phenylalanine, 4.60g of threonine, 1.50g of tryptophan, 10.60g of valine, 8.80g of arginine, 4.70g of histidine, 6.30g of glycine, 8.30g of alanine, Proline 7.10g, aspartic acid 2.50g, asparagine 0.55g, N-acetyl-L-cysteine 0.80g (corresponding to cysteine 0.60g), glutamic acid 5.70g, L- Ornithine hydrochloride 1.66 g (corresponding to L-ornithine 1.30 g), serine 3.70 g, N-acetyl-L-tyrosine 0.86 g (corresponding to
  • the vitamin may be directly added to the compound amino acid injection, or may be added to 250 ml of 5% glucose and sodium chloride injection or 250 ml of 0.9% sodium chloride injection.
  • a health care product oral liquid the component of which is a compound amino acid oral solution 1000ml (containing: isoleucine 8.80g, leucine 13.60g, lysine acetate 10.60g (corresponding to lysine 7.51g), Methionine 1.20g, phenylalanine 1.60g, threonine 4.60g, tryptophan 1.50g, valine 10.60g, arginine 8.80g, histidine 4.70g, glycine 6.30g, alanine 8.30g , valine 7.10g, aspartic acid 2.50g, asparagine 0.55g, N-acetyl-L-cysteine 0.80g (corresponding to cysteine 0.60g), glutamic acid 5.70g, L - ornithine hydrochloride 1.66 g (corresponding to L-ornithine 1.30 g), serine 3.70 g, N-acetyl-L-tyrosine 0.86 g (corresponding to tyrosine 0.
  • a health care product tablet comprising the following compound amino acids (containing: methionine 0.5 g, phenylalanine 0.5 g, threonine 1.5 g, tryptophan 0.5 g, proline 3.0 g, arginine) 3.0 g, glycine 1.8 g, alanine 2.2 g, valine 2.0 g, aspartic acid 0.8 g, asparagine 0.5 g, glutamic acid 1.5 g, L-ornithine hydrochloride 3.0 g, serine 1.2g), and vitamin B 6 3.0g, according to the conventional tablet excipients into a tablet suitable process to increase a number of films.
  • amino acids containing: methionine 0.5 g, phenylalanine 0.5 g, threonine 1.5 g, tryptophan 0.5 g, proline 3.0 g, arginine
  • the above injection preparations containing different doses of compound amino acids can be selected according to the patient's physical tolerance and body weight.
  • the principle is that the patient has small gastrointestinal symptoms. Dosage, when the patient's body is well tolerated and the weight is heavier, choose a larger dose. Under normal circumstances, 250ml of compound amino acid can be used.
  • oral preparations can be taken to consolidate or maintain efficacy after regular infusion therapy.
  • the content of the substance in each of the above-mentioned preparation examples is usually the daily dose used by the patient, and can be appropriately adjusted according to the condition of the patient.
  • amyotrophic lateral sclerosis Those who have been diagnosed as motor neuron disease or further clearly classified as amyotrophic lateral sclerosis (ALS) by well-known domestic hospitals (such as Union Hospital, Shanghai Huashan Hospital, Peking University Third Hospital, etc.) and compared with the World Neurology Alliance
  • the clinical diagnostic criteria for amyotrophic lateral sclerosis (EEC, 2000) and the guidelines for the diagnosis and treatment of amyotrophic lateral sclerosis in China (2012) were reviewed for re-diagnosis, and the diagnosis was not confirmed in the external hospital.
  • amyotrophic lateral sclerosis Clinical diagnostic criteria EEC, 2000
  • Chinese patients with amyotrophic lateral sclerosis diagnosis and treatment guidelines (2012) diagnosed patients, including clinically confirmed ALS 36 patients, clinically diagnosed ALS 8 patients, clinically possible ALS 4 patients.
  • Intravenous infusion (instillation) of the following pharmaceutical compositions is given once daily for 30 days for one course of treatment:
  • vitamin C 2.0 g, 10% potassium chloride 5 ml is formulated into the above pharmaceutical composition for intravenous infusion.
  • 0.9% sodium chloride injection can be replaced by 5% glucose sodium chloride injection 250ml or 10% according to the patient's condition Glucose injection 250ml.
  • glucose injection and insulin injection can be supplemented.
  • the amount of insulin injection is calculated per unit (1 u) of insulin compared to 4 g of glucose.
  • the compound amino acid injection used in clinical practice contains: 8.80g of isoleucine, 13.60g of leucine, 10.60g of lysine acetate (corresponding to 7.51g of lysine), and 1.20g of methionine.
  • the hydrochloride salt was 1.66 g (corresponding to L-ornithine 1.30 g), serine 3.70 g, and N-acetyl-L-tyrosine 0.86 g (corresponding to tyrosine 0.70 g).
  • the ventilator assisted breathing becomes free to breathe freely from the ventilator, or from the long-term need for ventilator assisted breathing to energy gap using ventilator assisted breathing;
  • ALSFRS-R Muscle Atrophic Lateral Sclerosis Functional Rating Scale
  • ALSFRS-R Muscle Atrophic Lateral Sclerosis Functional Rating Scale
  • the scale is simple, easy to operate, and widely used. Its sensitivity, reliability and stability have been widely recognized.
  • a commonly used scoring scale for assessing the progression and prognosis of amyotrophic lateral sclerosis, ALSFRS-R consists of 12 items: 1. language; 2. salivation; 3. swallowing; 4. writing; 5. cutting food, using Tableware; 6. Dressing and self-care; 7. Turning over and arranging bedding on the bed; 8. Walking; 9. Stair climbing; 10. Difficulty breathing; 11. Sitting breathing; 12. Respiratory insufficiency. Each score ranges from 0 to 4 points.
  • Functional scores ranged from 0 (severe impairment) to 48 (normal). The score is performed by a specialist who is proficient in the training. Because ALS is a progressive disease, it is not effective treatment Next, its ALSFRS-R showed a progressive decline, usually 5-6 points in 6 months and 10 points in 12 months.
  • Specific treatment options compound amino acid injection 500ml / day, intravenous infusion, 1 time / day; 5% glucose sodium chloride injection 250ml + vitamin B 6 3.0g + vitamin C 2.0g, once a day, intravenously.
  • Specific treatment options compound amino acid injection 500ml / day, intravenous infusion, 1 time / day; 5% glucose sodium chloride injection 250ml + vitamin B 6 3.0g + vitamin C 2.0g, once a day, intravenously.
  • the patient can only walk 200 meters when he is admitted to the hospital. After 2 weeks of treatment, he can walk independently for 3 kilometers. The symptoms of fatigue are improved, and the muscle strength of the left hand and upper limbs is obviously increased. At the time of discharge, the left hand grip strength was increased from Grade I to Grade III, and the muscle strength of both lower limbs was increased from Grade IV to Grade V.
  • Specific treatment options compound amino acid injection 500ml / day, intravenous infusion, 1 time / day; 5% glucose sodium chloride injection 250ml + vitamin B 6 5.0g + vitamin C 2.0g, once a day, intravenously.
  • the patient is ⁇ , male, 41 years old.
  • the onset time was March 2007, and the time of admission was 104 months.
  • the patient started with fatigue in the legs, in Shanghai Hospital of Integrated Traditional Chinese and Western Medicine (2007-03-29), Changzhou Second People's Hospital affiliated to Nanjing Medical University (2008-03-25), and Zhongshan Hospital affiliated to Fudan University (2008-04- 10) and Nanjing Brain Hospital (2015-05-21) diagnosed as motor neuron disease, parallel electromyography (2007-03-30, Shanghai Hospital of Integrated Traditional Chinese and Western Medicine, 0707431; 2008-03-25, Changzhou City Second People's Hospital, 14107), craniocerebral MRI (2006-12-29, Changzhou Wujin People's Hospital, 08339) inspection.
  • EMG the upper and lower extremity muscles and rectus abdominis muscles and sternocleidomastoid muscles see fibrillation positive apex waves; light contraction part of the examined muscle see MUP wide or see huge potential or waveform difference; The recruitment is reduced.
  • NCV The left ulnar nerve deep branch motion conduction CMAP amplitude is reduced; the residual motion and sensory nerve conduction velocity and amplitude normal range. The normal range of motor nerve F wave latency is not elicited.
  • Neurogenic damage to the EMG involving the upper and lower extremities and the rectus abdominis muscles as well as the trapezius and sternocleidomastoid muscles, the tongue muscle also has mild chronic damage changes.
  • Spinal anterior horn cells and sublingual nerve motor nuclear damage can be considered first.
  • Specific treatment options compound amino acid injection 500ml / day, intravenous infusion, 1 time / day; 5% glucose sodium chloride injection 250ml + vitamin B 6 5.0g + vitamin C 2.0g, once a day, intravenously.
  • Pre-hospital EMG EMG: upper and lower extremity muscles and rectus abdominis as well as trapezius and sternocleidomastoid muscles see fibrillation positive or wave tremor potential; light contraction part of the test muscle see MUP wide or See large potentials or supplement multi-phase potentials and irregular waves increase; re-contraction recruitment is reduced.
  • NCV CMAP amplitude of bilateral common nerve motor conduction decreased; residual motor and sensory nerve conduction velocity and amplitude normal range. The normal range of motor nerve F wave latency is not elicited.
  • Compound Amino Acid Injection 500ml / day, intravenous infusion, once / day; 1 5% glucose and sodium chloride injection 250ml + vitamin B 6 5.0g + vitamin C 2.0g, daily intravenous infusion.
  • the bilateral biceps muscles were atrophied, and the bilateral quadriceps, tibialis anterior muscles, and posterior muscles of the calves were atrophied.
  • the iliopsoas muscle strength is grade IV
  • the bilateral quadriceps muscle strength is grade IV
  • the left hind leg muscles muscle strength is grade III
  • the right calf posterior muscle group muscle strength is grade IV
  • bilateral anterior tibialis anterior muscle strength Level III The right foot is twisted and the back is weak.
  • the muscle tension of the limbs is low and the tension of the left toe muscle is increased.
  • the patient's sister is the same. Electromyography before admission: 1. The amplitude of the nerve conduction evoked potential of the right common sacral nerve is decreased; 2.
  • the distal latency of the motor nerve conduction of the bilateral sacral nerve is prolonged, and the amplitude of the evoked potential is decreased; 3.
  • the nerve conduction of the left common sacral nerve is tiny. Exercise response; 4.
  • Right small finger muscles can be seen under the resting beam potential, light contraction is normal size MUP, vigorous contraction is near interference phase; 5.
  • Left quadriceps, right anterior tibialis anterior muscle, left anterior tibialis muscle The examination showed neurogenic myoelectric changes; 6.
  • the right quadriceps were seen to be self-generating at rest, and the partial contraction was seen in light contraction.
  • bilateral median nerve movement conduction distal latency is prolonged;
  • the left common peroneal nerve which only showed a small motor response, could detect the corresponding motion potential wave, and most of the affected nerve conduction amplitude increased.
  • Electromyography (2016-02-16, Jiangsu Provincial People's Hospital, C20160181; 2016-03-28, Huashan Hospital affiliated to Fudan University, 58927), MRI of the cranial and cervical lumbosacral (2015-06-09, Gulou Hospital, cranial MRI +MRA; 2015-09, Zhongda Hospital affiliated to Southeast University, cranial MRI+MRA, neck, chest, lumbosacral, 964151XGT) and lung function (2016-02-04, Jiangsu Provincial Hospital of Traditional Chinese Medicine, KSXUGT16020402). I have been treated with oral rurubin, but the effect is not good.
  • EMG left lingual muscle see fibrillation, right tongue muscle is not examined; left first dorsal interosseous muscle, temporal flexor digitorum, lingual muscle, right temporal iliac crest flexor Wave; the right sternocleidomastoid muscle sees the tremor wave; the upper and lower limbs of the examined muscle see the insertion potential prolonged, the light contraction sees MUP wide with or without multiphase potential and irregular wave increase; rush contraction recruitment reduced.
  • NCV Normal range of motion and sensory nerve conduction velocity and amplitude. The normal range of the motor nerve F wave latency.
  • Blink Bilateral sacral sacral stimulation of the orbicularis muscle records the normal range of R1 and R2 latency. Neurogenic damage to myoelectric changes, mainly involving the tongue muscle, partial muscles of the upper limbs and sternocleidomastoid muscles are also slightly involved.
  • EMG EMG: bilateral lingual muscle see fibrillation wave; right tibialis anterior muscle and bilateral lingual muscle see positive sharp wave; light contraction part of the examined muscle see MUP wide or partial wide; heavy contraction recruitment cut back.
  • NUV The normal range of motion and sensory nerve conduction velocity and amplitude. Neurogenic damage to myoelectric changes, mainly involving the tongue muscle, and mild involvement of the upper and lower limbs and the trapezius muscle. Spinal anterior horn cells and sublingual nerve motor nuclear damage can be considered first.
  • EMG The right deltoid muscle and the right anterior tibialis anterior muscle can be seen in a large number of self-generated positions, and the small force contraction exercise unit potential time limit is widened. Contraction recruitment is a simple phase. The left sternocleidomastoid muscle small force contraction motor unit potential time widened, reduced contraction recruitment. A large number of self-generating bits can be seen when the right side T11 and T10 are quiet.
  • NCV 1. The right median nerve movement end latency is normal high limit, the conduction velocity is normal, the CMAP amplitude is decreased, the F wave is not extracted; the sensory conduction velocity is normal, and the SNAP amplitude is normal. 2.
  • the latency of the right ulnar nerve movement is prolonged, the conduction velocity is normal, the CMAP amplitude is decreased, and the F wave is not extracted; the sensory conduction velocity is normal, and the SNAP amplitude is normal. Extensive neurogenic damage.
  • Electromyography at discharge (2016-11-04): EMG: the upper and lower limbs were examined with the muscles and the lingual muscles and the fibrillation was positively pointed; for some of the examined muscles, the MUP was broad or partially wide; the retraction recruitment was reduced.
  • NCV The amplitude of the CMAP amplitude of the positive and ulnar nerve conduction on the right side is reduced; the residual motion and sensory nerve conduction velocity and the amplitude range are normal.
  • Neurogenic damage to myoelectrical changes affects the upper and lower extremities and the lingual muscles, and the trapezius muscle is also slightly involved. Spinal anterior horn cells and sublingual nerve motor nuclear damage can be considered first.
  • Compound Amino Acid Injection 500ml intravenous infusion, once daily; 0.9% sodium chloride injection 500ml + vitamin B 6 5.0g, intravenous infusion, once a day.
  • EMG Partial muscles of the upper limbs and the trapezius muscles see the positive wave of fibrillation; for the light contraction part of the muscle, the MUP is broad or partially wide; the recruitment of the systolic contraction is reduced.
  • NCV The median median nerve and ulnar nerve conduction CMAP amplitude decreased; residual motor and sensory nerve conduction velocity and amplitude normal range. Neurogenic damage to myoelectric changes, cumulative upper limbs and trapezius muscles and sternocleidomastoid muscles, both lower limb muscles are also slightly involved. Ridge Myeloid anterior horn cell damage can be considered first.
  • CV The amplitude of MCV and SCV of bilateral radial nerves decreased, and the remaining SCV and MCV of the remaining nerves were in the normal range.
  • RNS The left and right facial nerve, the right ulnar nerve, the right phrenic nerve, the orbicularis oculi muscle, the small finger muscle, and the short extensor muscle were recorded as distinct characteristic changes.

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Abstract

一种用于治疗运动神经元病的组合物及其用途。每单位该组合物含有L-鸟氨酸0.3～8g或者相当于L-鸟氨酸含量为0.3～8g的L-鸟氨酸盐，天冬氨酸0.5～5g，维生素B 6 2～20g；该组合物能够改善甚至逆转运动神经元病的进展，可用于制备治疗运动神经元病的药物或保健品。该组合物长期使用安全无副作用，治疗费用低，效果好，适于临床推广。

Description

一种用于治疗运动神经元病的组合物及其用途 技术领域
本发明属于制药领域，涉及一种用于治疗运动神经元病的组合物及其用途。
背景技术
运动神经元病(motor neuron disease，MND)，是一组病因尚未明确的选择性侵犯脊髓前角细胞、脑干运动神经元、皮质椎体细胞及椎体束的慢性进行性变性疾病，其病理特征为进行性上、下运动神经元的变性、坏死及凋亡。临床上兼有上和(或)下运动神经元受损表现，为肌无力、肌肉萎缩和椎体束征的不同组合，最终常因呼吸衰竭至死，感觉和***功能一般不受影响。由于症状和体征的组合不同，形成不同类型的运动神经元病，包括肌萎缩侧索硬化(amyotrophic lateral sclerosis，ALS)、脊肌萎缩症(spinal muscular atrophy，SMA)、原发性侧索硬化(primary lateral sclerosis，PLS)和进行性延髓麻痹(progressive bulbar palsy，PBP)等，其中ALS是慢性运动神经元病的最常见类型，俗称“渐冻人症”。
目前对本病的病因及发病机制仍不明确。其中比较公认的有自由基氧化学说、兴奋性氨基酸毒性、神经营养因子障碍、自身免疫机制、病毒感染及环境因素等。各种假说均有一定的证据支持，当前较为集中的认识是在遗传背景基础上是氧化损害和兴奋性毒性作用共同损害了运动神经元，主要是影响了线粒体和细胞骨架的结构和功能。
“渐冻人症”目前尚无明确有效的治疗方法，患者的平均存活时间只有2-5年。被世界卫生组织列为五大绝症之一。在全球每90分钟就夺去1名“渐冻人”患者的生命，据统计，到2010年底，在我国大约有20多万渐冻人患者。
目前对于运动神经元病的治疗措施主要为了减轻症状、延缓病情的进展及提高患者的生存质量。对症用药主要有：力如太(又叫力鲁唑，Riluzole)——目前唯一一个美国食品药品监督局(FDA)批准的用于治疗ALS的药物，是一种抗谷氨酸毒性的药物，也是目前唯一一个证明对动物模型有效、临床有效的药物，其可以延缓病情发展，也仅仅能使患者的生存期延长半年左右。其他用药还有：甲钴安、维生素B族、维生素E 及各种神经营养药物等。中医将其归属于“痿症”，病机为五脏虚损、精津不足、气血亏虚、肌肉筋脉失养、脾胃虚损。在治疗上辩证论治，针药并举，注重以调理脾胃功能，益脾补虚，调补心、肺、肝、肾四脏虚损。使患者症状得到改善，病情发展延缓，运动神经元病痛得到减轻。
目前尚无一种对运动神经元病安全有效且成本低廉的药物或保健品。
发明内容
本发明的目的是提供一种用于治疗运动神经元病的组合物。
本发明的另一目的是提供上述组合物的用途。
本发明还有一个目的是提供采用上述组合物治疗运动神经元病的方法。
本发明的目的是通过下列技术方案实现的：
一种用于治疗运动神经元病的组合物，每单位该组合物中含有下列用量比例关系的物质：
L-鸟氨酸0.3～8g或者相当于L-鸟氨酸含量为0.3～8g的L-鸟氨酸盐，天冬氨酸0.5～5g，维生素B6 2～20g；
优选L-鸟氨酸0.325～8g或者相当于L-鸟氨酸含量为0.325～8g的L-鸟氨酸盐，天冬氨酸0.625～5g，维生素B6 3～20g；
进一步优选L-鸟氨酸0.5～8g或者相当于L-鸟氨酸含量为0.5～8g的L-鸟氨酸盐，天冬氨酸1～5g，维生素B6 6～20g；
或者
进一步优选L-鸟氨酸0.325～0.65g或者相当于L-鸟氨酸含量为0.325～0.65g的L-鸟氨酸盐，天冬氨酸0.625～1.25g，维生素B6 3～10g。
所述的组合物，其中每单位该组合物中还含有下列物质中的任意一种或多种：精氨酸，异亮氨酸，亮氨酸，赖氨酸，蛋氨酸，苯丙氨酸，苏氨酸，色氨酸，缬氨酸，组氨酸，甘氨酸，丙氨酸，脯氨酸，天冬酰胺，半胱氨酸，谷氨酸，丝氨酸，酪氨酸，维生素B1，维生素B2，维生素B3，泛酸，生物素，叶酸，维生素B12，维生素C，KCl；
上述氨基酸可以采用氨基酸的各种可溶性盐或者其衍生物替代。
比如：赖氨酸采用赖氨酸醋酸盐替代，半胱氨酸采用N-乙酰-L-半胱氨酸替代，酪氨酸采用N-乙酰-L-酪氨酸替代；
上述任意一种或多种物质的用量对应以下用量比例关系：
各氨基酸的用量比例关系分别是：精氨酸2.0～10g，异亮氨酸2.0～10g，亮氨酸3.0～15g，相当于赖氨酸含量为1.5～10g的赖氨酸醋酸盐，蛋氨酸0.2～3g，苯丙氨酸0.3～3g，苏氨酸1.0～10g，色氨酸0.3～3g，缬氨酸2.5～15g，组氨酸1.0～8g，甘氨酸1.5～8g，丙氨酸2.0～10g，脯氨酸1.5～8g，天冬酰胺0.1～3g，相当于半胱氨酸含量为0.1～3g的N-乙酰-L-半胱氨酸，谷氨酸1.0～10g，丝氨酸0.5～5g，相当于酪氨酸含量为0.1～3g的N-乙酰-L-酪氨酸；
维生素的用量比例关系分别是：维生素B1 1.0～4.0mg，维生素B2 1.0～4.0mg，维生素B3 10～40mg，泛酸3.0～10mg，生物素0.1～0.4mg，叶酸0.1～0.8mg，维生素B12 2.0～12μg；维生素C 1.0-6.0g；
KCl的用量为10％KCl 5～10ml；
优选：
各氨基酸的用量比例关系分别是：精氨酸2.2～4.4g，异亮氨酸2.2～4.4g，亮氨酸3.4～6.8g，相当于赖氨酸含量为1.8775～3.755g的赖氨酸醋酸盐，蛋氨酸0.3～0.6g，苯丙氨酸0.4～0.8g，苏氨酸1.15～2.3g，色氨酸0.375～0.75g，缬氨酸2.65～5.3g，组氨酸1.175～2.35g，甘氨酸1.575～3.15g，丙氨酸2.075～4.15g，脯氨酸1.775～3.55g，天冬酰胺0.1375～0.275g，相当于半胱氨酸含量为0.15～0.3g的N-乙酰-L-半胱氨酸，谷氨酸1.425～2.85g，丝氨酸0.925～1.85g，相当于酪氨酸含量为0.175～0.35g的N-乙酰-L-酪氨酸；
维生素的用量比例关系分别是：维生素B1 1.0～4.0mg，维生素B2 1.0～4.0mg，维生素B3 10～40mg，泛酸3.0～10mg，生物素0.1～0.4mg，叶酸0.1～0.8mg，维生素B12 2.0～12μg；维生素C 1.0-6.0g；
KCl的用量为10％KCl 5～10ml；
或者优选：
各氨基酸的用量比例关系分别是：精氨酸3.0～10g，异亮氨酸3.0～10g，亮氨酸5.0～15g，相当于赖氨酸含量为3.0～10g的赖氨酸醋酸盐，蛋氨酸0.5～3g，苯丙氨酸0.5～3g，苏氨酸3.0～10g，色氨酸0.5～3.0g，缬氨酸5.0～15g，组氨酸3.0～8.0g，甘氨酸3.0～8.0g，丙氨酸3.0～10g，脯氨酸3.0～8.0g，天冬酰胺0.1～3.0g，相当于半胱氨酸含量为0.1～3.0g的N-乙酰-L-半胱氨酸，谷氨酸3.0～10g，丝氨酸0.5～5.0g，相当于酪氨酸含量为0.1～3g的N-乙酰-L-酪氨酸；
维生素的用量比例关系分别是：维生素B1 2.0～4.0mg，维生素B2 2.0～4.0mg，维生 素B3 20～40mg，泛酸6.0～10mg，生物素0.2～0.4mg，叶酸0.2～0.8mg，维生素B12 4.0～12μg；维生素C 2.0-6.0g。
具体地说，所述的组合物，每单位该组合物中含有下列用量比例关系的物质：
异亮氨酸2.2g，亮氨酸3.4g，赖氨酸醋酸盐2.65g(相当于赖氨酸1.8775g)，蛋氨酸0.3g，苯丙氨酸0.4g，苏氨酸1.15g，色氨酸0.375g，缬氨酸2.65g，精氨酸2.2g，组氨酸1.175g，甘氨酸1.575g，丙氨酸2.075g，脯氨酸1.775g，天冬氨酸0.625g，天冬酰胺0.1375g，N-乙酰-L-半胱氨酸0.2g(相当于半胱氨酸0.15g)，谷氨酸0或1.425g，L-鸟氨酸盐酸盐0.415g(相当于L-鸟氨酸0.325g)，丝氨酸0.925g，N-乙酰-L-酪氨酸0.215g(相当于酪氨酸0.175g)，维生素B6 3.0～5.0g，10％KCl 0或5～10ml，维生素C 0或2.0～6.0g；或者
异亮氨酸4.4g，亮氨酸6.8g，赖氨酸醋酸盐5.3g(相当于赖氨酸3.775g)，蛋氨酸0.6g，苯丙氨酸0.8g，苏氨酸2.3g，色氨酸0.75g，缬氨酸5.3g，精氨酸4.4g，组氨酸2.35g，甘氨酸3.15g，丙氨酸4.15g，脯氨酸3.55g，天冬氨酸1.25g，天冬酰胺0.275g，N-乙酰-L-半胱氨酸0.4g(相当于半胱氨酸0.3g)，谷氨酸0或2.85g，L-鸟氨酸盐酸盐0.83g(相当于L-鸟氨酸0.65g)，丝氨酸1.85g，N-乙酰-L-酪氨酸0.43g(相当于酪氨酸0.35g)，维生素B6 3.0～10g，10％KCl 0或5～10ml，维生素C 0或2.0～6.0g。
上述任一组合物还可以含有适量的5％葡萄糖氯化钠注射液(5％GNS)或0.9％氯化钠注射液(0.9％NS)或10％葡萄糖注射液。
对于含有葡萄糖的该组合物还可加入胰岛素，胰岛素的用量为每一个单位(1u)胰岛素比3～5g葡萄糖，优选每一个单位(1u)胰岛素比4g葡萄糖。
更进一步，作为上述组合物的优选方案，该组合物的具体配方为：
0.9％氯化钠注射液250ml+维生素B6 3.0g或5.0g+复方氨基酸注射液250ml或500ml；或者
0.9％氯化钠注射液250ml+维生素B6 3.0g或5.0g+复方氨基酸注射液250ml或500ml+维生素C 2.0g；或者
0.9％氯化钠注射液250ml+维生素B6 3.0g或5.0g+复方氨基酸注射液250ml或500ml+10％氯化钾5ml；或者
0.9％氯化钠注射液250ml+维生素B6 3.0g或5.0g+复方氨基酸注射液250ml或500ml+维生素C 2.0g+10％氯化钾5ml；或者
5％葡萄糖氯化钠注射液250ml+胰岛素注射液4u+维生素B6 3.0g或5.0g+维生素C  2.0g+10％氯化钾5ml+复方氨基酸注射液250ml；或者
10％葡萄糖注射液250ml+胰岛素注射液8u+维生素B6 3.0g或5.0g+维生素C 2.0g+10％氯化钾5ml+复方氨基酸注射液250ml；
其中：
上述复方氨基酸注射液，每1000ml中含有：异亮氨酸8.80g，亮氨酸13.60g，赖氨酸醋酸盐10.60g(相当于赖氨酸7.51g)，蛋氨酸1.20g，苯丙氨酸1.60g，苏氨酸4.60g，色氨酸1.50g，缬氨酸10.60g，精氨酸8.80g，组氨酸4.70g，甘氨酸6.30g，丙氨酸8.30g，脯氨酸7.10g，天冬氨酸2.50g，天冬酰胺0.55g，N-乙酰-L-半胱氨酸0.80g(相当于半胱氨酸0.60g)，谷氨酸5.70g，L-鸟氨酸盐酸盐1.66g(相当于L-鸟氨酸1.30g)，丝氨酸3.70g，N-乙酰-L-酪氨酸0.86g(相当于酪氨酸0.70g)。
上述的任一组合物的剂型为药学上允许的任意剂型或保健品允许的任意剂型；该组合物的剂型优选为注射剂、口服液、片剂、颗粒剂、胶囊剂、冲剂。相应的剂型可以含有适合该剂型的常用辅料，如水、硬脂酸镁、糊精等，这些辅料均是本领域技术人员所公知的。
上述的任一组合物在制备治疗运动神经元病的药物或保健品中的应用。
其中：所述运动神经元病包括肌萎缩侧索硬化、脊肌萎缩症、原发性侧索硬化、进行性延髓麻痹，优选肌萎缩侧索硬化。
一种治疗运动神经元病的方法，该方法采用注射或口服的方式给予患者上述组合物；所述注射方式优选静脉注射。
所述的方法中每个疗程为采用注射或口服的方式给予患者上述组合物10-40天，优选15-30天；一个疗程结束后，可以根据治疗需要在休息适当时间(如10-15天)后继续进行下一个疗程或者不进行下一个疗程。
进一步，对于吞咽困难、呛咳、或者进食困难的患者可补充葡萄糖注射液及胰岛素。
需要说明的是，根据临床观察，维生素B6每天的用量小于1.0g治疗效果不明显。另外，直接静脉推注末稀释的维生素B6治疗效果不明显。
本发明所述的每单位组合物中各物质的含量也可以采用质量份等方式表述，不影响该组合物中各物质含量的比例关系。所述的每单位一般指病人一日使用的剂量，可根据病情作适当的调整。在制备成不同剂型时可以将每日使用的剂量制成一个包装如一瓶或一袋注射液，也可以根据使用情况制成若干个基本单元如以片剂的形式制成若干片，等等。
本发明中各氨基酸优选L型氨基酸。
本发明组合物对运动神经元病的治疗机制探讨：
静息电位是指细胞在未受刺激时(静息状态下)存在于细胞膜内、外两侧的电位差。众所周知，静息电位存在于神经和肌肉纤维内。J.Bernstein于1902年首次提出神经细胞膜两边的K+分布的不相等以及膜对钾离子的选择通透性是静息电位的产生原因。静息神经细胞对K+是高通透的，对Na+则很低，正是这种选择性通透使膜内外形成K+浓度梯度而产生跨膜电位差。可见细胞膜内、外离子的不均匀分布以及在安静状态下对不同离子的通透性不同是静息电位产生的前提条件。细胞外的Na+浓度高于细胞内，而细胞内K+浓度远高于细胞外，因此在细胞膜的两侧存在离子浓度差；另外，还会存在电位差。离子的扩散动力就取决于浓度差和电位差，细胞在安静状态下，只是对K+有通透性，对Na+和其他离子的通透性很小。K+在浓度差的动力下向膜外扩散，由于K+是正离子，向外扩散形成的外正内负的电位差又会阻止K+的进一步扩散，当促使K+外流的浓度差动力和阻止K+外流的电位差阻力相等时，K+的外流停止，此时的跨膜电位称为K+平衡电位。影响静息电位水平的因素主要有：①细胞外K+浓度可影响静息电位的大小，如细胞外K+浓度升高，细胞内K+浓度差降低，K+外流的量减少，静息电位减少；②膜对K+和Na+的相对通透性可影响静息电位的大小，如膜对K+的通透性增大，则静息电位增大，如膜对Na+的通透性增大，则静息电位将减小；③钠泵活动的水平对静息电位有影响。
动作电位，是指可兴奋细胞受到刺激时，在静息电位的基础上产生的一次迅速可扩布性的电位变化。动作电位产生的机制为：细胞外的Na+浓度比细胞内高，Na+顺着浓度差就有内流的趋势，细胞在安静状态下，对Na+的通透性小，Na+内流的量也就很少。当细胞受到刺激后，细胞膜上少量的Na+通道被激活开放，Na+顺着浓度差和电位差内流，膜内的负电位值逐渐变小，发生去极化，当去极化到达一定的程度时，膜上钠通道大量被激活开放，大量的Na+内流，从而爆发动作电位。使膜对Na+通透性突然增大的临界膜电位，称为阈电位。阈电位比静息电位小约10-20mv，神经细胞的阈电位约为-55mv。刺激必须是膜内负电位值减少到阈电位时，才能爆发动作电位。由于Na+是顺着浓度差和电位差进行的扩散，Na+内流速度很快，膜内负电位值迅速变小、消失，并且进一步转为正电位，膜内形成的正电位对Na+内流形成电场阻力，阻止Na+内流，促使Na+内流的力量(浓度差)与阻止Na+内流的力量(电场阻力)相等时，Na+内流停止，这时动作电位达到最大幅值，即为Na+的电-化学平衡电位，形成动作电位的上升支，钠通道开放时间短，很快失活关闭，这时细胞膜对K+的通透性增大，大量K+顺着浓度差和电位差迅速外 流，使膜内电位从正值变为负值，出现复极化，恢复到静息状态水平，形成动作电位的下降支。简言之，动作电位的上升支就是Na+内流形成的电-化学平衡电位，动作电位的下降支就是K+外流形成的电-化学平衡电位。细胞在发生动作电位后，膜电位基本恢复到静息状态水平，但是离子分布没有恢复，细胞外有过多的K+，细胞内有过多的Na+，这时将激活细胞膜上的钠泵，通过钠泵的作用，将细胞外过多K+的泵入细胞内，同时将细胞内过多的Na+泵出细胞外，恢复原来的静息状态水平，为下一次兴奋做好准备。
氨基酸是构成生物体蛋白质并同生命活动有关的最基本的物质，是在生物体内构成蛋白质分子的基本单位，与生物的生命活动有着密切的关系。它在抗体内具有特殊的生理功能，是生物体内不可缺少的营养成分之一。其在人体内通过代谢可以发挥下列一些作用：①合成蛋白质及核酸；②变成酸、激素、抗体、肌酸等含氮物质；③转变为碳水化合物和脂肪；④氧化成二氧化碳和水及尿素，产生能量。
L-鸟氨酸是非蛋白氨基酸，在生物体内主要参与尿素循环，对体内氨态氮的排出有重要作用。在尿素循环中，氨甲酰磷酸合成酶Ⅰ是尿素循环中的酶，存在于线粒体中，以氨为氮源，需要N-乙酰谷氨酸，生成的氨甲酰磷酸用来合成尿素；氨甲酰磷酸合成酶Ⅱ存在于胞质溶胶中，利用谷氨酰胺作为氮源，不需要N-乙酰谷氨酸，合成的氨甲酰磷酸用来合成嘧啶。由氨甲酰磷酸合成酶Ⅰ催化的第一步反应是尿素循环的限速步骤。氨甲酰磷酸合成酶Ⅰ被N-乙酰谷氨酸别构酶活化。该代谢物是由谷氨酸和乙酰CoA在N-乙酰谷氨酸合成酶催化下合成。当氨基酸降解速率增加时，作为转氨作用的结果，谷氨酸的浓度也随之增加，谷氨酸浓度的增加促进了N-乙酰谷氨酸的合成，结果活化了氨甲酰磷酸合成酶，使尿素合成速率加快。因此氨基酸降解产生的过量氮，就被有效的排出体外。由于精氨酸是N-乙酰谷氨酸合成酶的激活剂，因此精氨酸浓度的增高，也会加速尿素的合成。
天冬氨酸通过脱氨生成草酰乙酸而促进三羧酸循环，故而天冬氨酸是三羧酸循环中的重要成分。并且天冬氨酸还在鸟氨酸循环和核苷酸合成中起重要作用，是多种氨基酸及嘌呤、嘧啶碱基的合成前体。它对细胞亲和力很强，可作为钾、镁离子载体，向心肌输送电解质，促进细胞去极化，维持心肌收缩能力，同时可降低心肌耗氧量，在冠状动脉循环障碍引起缺氧时，对心肌有保护作用。也就是说天冬氨酸能直接参与尿素循环并参与三羧酸循环及肝细胞内核酸的合成，有利于修复被损伤的肝细胞。此外，由于天冬氨酸对肝细胞内三羧酸循环代谢过程的间接促进作用，并提供能量代谢的中间产物，促进了肝细胞的能量生成，使被损伤的肝细胞的各项功能得以迅速恢复。所以L-鸟氨酸和 天冬氨酸合用可以刺激肝尿素循环活性和促进谷氨酰胺合成，大大增强肝脏排毒功能，迅速降低血氨，促进肝细胞自身的修复和再生。因此，氨基酸在人体内的存在，不仅能提供合成蛋白质的重要原料，而且对于促进生长，进行正常代谢，维持生命提供了物质基础。
B族维生素是水溶性维生素，包括维生素B1、维生素B2、维生素B6、维生素B12、烟酸、泛酸、叶酸等，是推动体内代谢，把糖、脂肪、蛋白质等转化成热量时不可缺少的物质。它们具有协同作用，调节新陈代谢，增进免疫***促进细胞生长和***。维生素B6可能是所有维生素B族中最重要的一种。维生素B6又名吡哆素，包括吡哆醇、吡哆醛和吡哆胺3种化合物。在动物组织中吡哆醇可转化为吡哆醛或吡哆胺，且维生素B6多以吡哆醛和吡哆胺形式存在与动物组织中。吡哆醛和吡哆胺，吡哆醛磷酸和吡哆胺磷酸都可以互变，最后都以活性较强的吡哆醛磷酸和吡哆胺磷酸形式存在于组织中，参加转氨作用。一般人体的肌肉里含有全身70％～80％的维生素B6。维生素B6在蛋白、脂质和碳水化合物的代谢中发挥着关键的作用。所以，大量损耗维生素B6的人会出现包括氨基酸代谢紊乱。维生素B6是氨基酸的代谢与合成的重要辅酶，并参与不饱和脂肪酸的代谢等生理过程，是机体内许多重要酶***的辅酶，是动物正常发育、细菌和酵母繁殖所必需的营养成分。另外，维生素B6还是一种天然的利尿剂，利尿就能解毒，静脉输入维生素B6 5g，大约能利出尿液380ml左右。维生素B6是人体氨基酸代谢、神经递质γ-氨基丁酸(GABA)和谷氨酸(Glu)的辅酶，现已知肝脏有60多种酶需要维生素B6参与，在促进机体正常酶代谢方面起到十分重要的作用，且维生素B6在体内的半衰期短，很快就排出体外。并且吡哆醛磷酸还有一特殊的功能，其可以促进氨基酸和钾进入细胞的速率。
钾是体内最重要的无机阳离子之一，在机体电解质中的含量仅次于钠，其中98％存在于细胞内，存在于细胞外液的仅占2％，血清钾浓度为3.5-5.5mmol/L。细胞内外钾浓度相差悬殊是靠细胞膜Na+-K+-ATP酶耗能转运来维持的。钾是全身所有器官功能作用的重要物质基础，参与全身所有的器官作用。其生理功能有：①参与细胞内糖和蛋白质的代谢；②维持细胞内的渗透压和调节酸碱平衡；③维持细胞膜静息电位，静息膜电位主要取决于细胞膜对K+的通透性和细胞膜内外K+的浓度差；④维持神经肌肉的兴奋性，高钾使神经肌肉兴奋性增高，低钾使兴奋性降低；⑤维持正常心肌收缩运动的协调。
例如：乙酰胆碱的突触传递过程。乙酰胆碱是脊椎动物神经肌肉接头(运动终板)上的兴奋性神经递质。乙酰胆碱是在胆碱能神经元的轴突末梢轴浆中合成。胆碱和乙酰 辅酶A在胆碱乙酰基转移酶的作用下生成乙酰胆碱。神经细胞不能合成胆碱，主要靠血循环供给，借助细胞膜上的专一性载体——胆碱转运体摄取到细胞中。肝脏中合成的胆碱酯、胶质细胞中储备的胆碱以及神经末梢释放的乙酰胆碱水解产生的胆碱也可以成为乙酰胆碱合成中胆碱的来源。并且乙酰胆碱合成后被包装在突触小泡内，每个小泡约有103-104分子的乙酰胆碱，就在突触前轴突质膜附近有大量这样的突触小泡。动作电位的到达，激发突触前膜大大增加对Ca2+的通透性，Ca2+顺其离子浓度梯度流入轴浆。由于细胞内Ca2+的增加，促进了突触小泡与质膜的融合，从而增加乙酰胆碱释放到突触间隙。通过这种机制，在对1个动作电位所引起的反应中，可有几百个突触小泡排出乙酰胆碱到一个典型的神经肌肉突触接头的突触间隙。结果是局部的乙酰胆碱浓度大大增加，足以使突触后细胞的质膜中的1种蛋白质即乙酰胆碱受体“感觉到”。这种神经递质结合到许多受体分子上，激发突触后细胞发生动作电位。乙酰胆碱随后为突触间隙中的1种称为乙酰胆碱酯酶迅速降解成乙酸和胆碱，同时突触后膜迅速恢复至静息电位。并且在这一过程中，乙酰胆碱的作用同时增加了膜对Na+和K+的通透性。由于突触后膜的电化学梯度比K+的大一些，结果Na+的向内流动导致去极化，使跨膜电位崩溃。只要有足够数目的受体分子结合了神经递质，这种跨膜电位的局部扰动就足以在受体所在的神经膜或肌膜上引发出1个新的动作电位。因而在一定时刻被占据受体的数目支配了Na+的内向流动量，以及由此决定的膜电位变化的大小。结合于突触后膜的乙酰胆碱酯酶迅速催化乙酰胆碱水解，递质-受体复合物的数目很快减少，膜复极化，准备接待新的动作电位触发突触前膜释放更多量子单位的乙酰胆碱。
一般神经元产生的静息电位、动作电位、发生器电位和突触电位都有赖于血脑屏障主动转运形成的离子梯度，而且神经冲动的传递和准确再现也有赖于血脑屏障对神经元和神经纤维的屏蔽作用。有资料显示，运动神经元病患者脑脊液中的谷氨酸水平比80％对照组高3倍。且细胞外过高的谷氨酸浓度，会过度刺激其受体，对中枢神经***产生明显的毒性作用。但是使用本发明后发现，部分病人脑脊液中的谷氨酸水平明显下降，运动神经元得到修复，患者症状明显得到改善。原因有以下一种或几种：①本发明中，体内过高的谷氨酸和本发明中的半胱氨酸以及甘氨酸可以生成谷胱甘肽，清除体内的自由基，减轻运动神经元病患者的症状。②在肝脏中，过高的谷氨酸在谷氨酸脱氢酶(辅酶是NAD+或NADP+)的作用下氧化脱氨基生成α-酮戊二酸和氨，过多的氨可以与谷氨酸结合生成谷氨酰胺，谷氨酰胺和本发明中的天冬氨酸在氨甲基酰磷酸合成酶Ⅱ作用下合成嘧啶核苷酸，并且谷氨酰胺也可以和本发明中的甘氨酸以及天冬氨酸合成嘌呤核苷 酸，而且在肝脏胞液中谷氨酸与本发明中的甘氨酸和天冬氨酸参与嘌呤核苷酸从头合成，为体内核苷酸提供来源。嘧啶核苷酸和嘌呤核苷酸的合成，促进蛋白质合成，修复受损的神经元细胞，并且谷氨酸氧化脱氨基生成的多余氨由L-鸟氨酸激活肝细胞内尿素循环排出体外。③生成的谷氨酰胺能直接通过血脑屏障，分解成氨和谷氨酸，虽然在胞外过高的谷氨酸浓度对中枢神经***产生明显的毒性作用，但是胞内谷氨酸是哺乳动物中枢神经***含量最丰富的兴奋性神经递质，参与神经***多种重要功能的调节，对神经发育、突触可塑性的维持、神经元回路的形成及学***衡、使细胞膜静息电位增大、使神经肌肉兴奋性增高、使正常心肌收缩运动的得到协调。
总而言之，由于本发明中含有各种各样的氨基酸，其能够为血液提供新鲜的营养，通过氨基酸代谢以及血液循环能促进了受损神经细胞的再生，改善其代谢微环境，增强了神经元存活能力，本发明提供了机体新陈代谢的底物与强劲的动能，缓解了患者的病情，甚至能够逆转病情。并且鸟氨酸和天冬氨酸可以刺激肝尿素循环活性，通过尿素循环可将氨基酸代谢过程中产生的大量的氨排出体外。生物体内无论是神经调节还是激素调节，最终都是通过酶起作用。所以本发明中添加的大剂量维生素B6为人体氨基酸代谢、神经递质γ-氨基丁酸(GABA)和谷氨酸(Glu)的提供了充足的辅酶。虽然运动神经元病患者脑脊液中的谷氨酸水平偏高，但是使用本发明后，脑脊液中的谷氨酸可以转化为谷氨酰胺和谷胱甘肽。①人体通过谷氨酰胺可以从脑、肌肉等组织向肝或肾转运氨。谷氨酰胺没有毒性，是人体迅速解除氨毒的一种方式，在本病中也是迅速解除胞外过高的谷氨酸浓度对中枢神经***产生的明显毒性作用，同时储藏和运输氨。当运至肝脏中，谷氨酰胺将氨释放出来以合成尿素；当运至肾脏中，谷氨酰胺将氨释放出来直接随尿排出；运至各种组织中可用于合成氨基酸和嘌呤、嘧啶等含氮物质。也就是说本发明可以促进谷氨酰胺的合成，解除胞外过高的谷氨酸浓度对中枢神经***产生的明显毒性作用，并且谷氨酰胺能直接通过血脑屏障，为脑神经细胞的修复提供部分氨基酸、嘌呤和嘧啶。②谷胱甘肽的合成可以有效的清除体内的自由基，减轻运动神经元病患者的症状。且本发明中的氨基酸也为神经营养因子提供能量以及原料，修复受损的神经细胞。虽然在此过程中氨基酸代谢产生的大量氨，但是由于L-鸟氨酸的存在，L-鸟氨酸作为尿素循 环的反应底物，迅速激活肝细胞内的尿素循环，将机体产生的有害氨通过尿素排除体外，保证了机体正常的代谢。由于本发明中含有天冬氨酸，其是多种氨基酸及嘌呤、嘧啶碱基的合成前体，并且它对细胞亲和力很强，可作为钾、镁离子载体，向心肌输送电解质，促进细胞去极化，维持心肌收缩能力。其不但可以为神经营养因子提供能量以及原料，修复受损的神经细胞，而且可以促进K+进入神经元细胞，维持心肌收缩能力。并且和L-鸟氨酸联合使用，可以刺激肝尿素循环活性大大增强肝脏排毒功能，迅速降低血氨，促进肝细胞自身的修复和再生，从而增强了人体自身免疫能力，从本质上治疗运动神经元病，且本发明没任何毒副作用、治疗费用低，是运动神经元病患者首选药物。
本发明的有益效果：
本发明提供的组合物能够缓解甚至逆转运动神经元病的发病过程，基本上能够改善运动神经元病患者的临床症状，甚至能正常生活，具有较好的治疗效果，而且该组合物原料为食源性物质，长期服用没有毒副作用，治疗费用低，对运动神经元病患者来说基本没有经济负担，适合临床推广使用。
附图说明
图1是病例1肌电图报告单。
图2是病例3在北大第三医院确诊ALS诊断证明书。
图3是病例4肌电图报告单。
图4是病例5肌电图报告单。
具体实施方式
以下通过实施例对本发明作进一步的阐述。
一、药物组合物制备实施例
一般性说明：实施例中各组合物制剂的工艺按相应制剂的常规工艺配制即可。
实施例1
一种药物组合物，将相当于L-鸟氨酸2.5g的L-鸟氨酸盐酸盐约3.19g，天冬氨酸1.5g以及维生素B6 10g，加入到5％葡萄糖氯化钠注射液250ml中即可。
实施例2
一种药物组合物，将L-鸟氨酸盐酸盐0.415g(相当于L-鸟氨酸0.325g)，天冬氨酸 0.625g以及维生素B6 3.0g，加入到5％葡萄糖氯化钠注射液250ml中即可。
实施例3
一种药物组合物，将L-鸟氨酸盐酸盐0.83g(相当于L-鸟氨酸0.65g)，天冬氨酸1.25g，维生素B6 5.0g，加入到0.9％氯化钠注射液250ml中。
实施例4
一种药物组合物，其组分为复方氨基酸注射液250ml[含有异亮氨酸2.2g，亮氨酸3.4g，赖氨酸醋酸盐2.65g(相当于赖氨酸1.8775g)，苯丙氨酸0.4g，苏氨酸1.15g，色氨酸0.375g，精氨酸2.2g，组氨酸1.175g，甘氨酸1.575g，丙氨酸2.075g，脯氨酸1.775g，天冬氨酸0.625g，天冬酰胺0.1375g，N-乙酰-L-半胱氨酸0.2g(相当于半胱氨酸0.15g)，L-鸟氨酸盐酸盐0.415g(相当于L-鸟氨酸0.325g)，丝氨酸0.925g，N-乙酰-L-酪氨酸0.215g(相当于酪氨酸0.175g)]，以及维生素B6 3.0g，加入到0.9％氯化钠注射液250ml中。
实施例5
一种药物组合物，其组分为复方氨基酸注射液250ml[含有异亮氨酸2.2g，亮氨酸3.4g，赖氨酸醋酸盐2.65g(相当于赖氨酸1.8775g)，蛋氨酸0.3g，苯丙氨酸0.4g，苏氨酸1.15g，色氨酸0.375g，缬氨酸2.65g，精氨酸2.2g，组氨酸1.175g，甘氨酸1.575g，丙氨酸2.075g，脯氨酸1.775g，天冬氨酸0.625g，天冬酰胺0.1375g，N-乙酰-L-半胱氨酸0.2g(相当于半胱氨酸0.15g)，谷氨酸1.425g，L-鸟氨酸盐酸盐0.415g(相当于L-鸟氨酸0.325g)，丝氨酸0.925g，N-乙酰-L-酪氨酸0.215g(相当于酪氨酸0.175g)]，以及维生素B6 3.0g，加入到0.9％氯化钠注射液250ml中。
实施例6
一种药物组合物，其组分为复方氨基酸注射液250ml[含有异亮氨酸2.2g，亮氨酸3.4g，赖氨酸醋酸盐2.65g(相当于赖氨酸1.8775g)，蛋氨酸0.3g，苯丙氨酸0.4g，苏氨酸1.15g，色氨酸0.375g，缬氨酸2.65g，精氨酸2.2g，组氨酸1.175g，甘氨酸1.575g，丙氨酸2.075g，脯氨酸1.775g，天冬氨酸0.625g，天冬酰胺0.1375g，N-乙酰-L-半胱氨酸0.2g(相当于半胱氨酸0.15g)，谷氨酸1.425g，L-鸟氨酸盐酸盐0.415g(相当于 L-鸟氨酸0.325g)，丝氨酸0.925g，N-乙酰-L-酪氨酸0.215g(相当于酪氨酸0.175g)]，以及维生素B6 5.0g，维生素C 2.0g，加入到0.9％氯化钠注射液250ml中。
实施例7
一种药物组合物，其组分为复方氨基酸注射液250ml[含有异亮氨酸2.2g，亮氨酸3.4g，赖氨酸醋酸盐2.65g(相当于赖氨酸1.8775g)，蛋氨酸0.3g，苯丙氨酸0.4g，苏氨酸1.15g，色氨酸0.375g，缬氨酸2.65g，精氨酸2.2g，组氨酸1.175g，甘氨酸1.575g，丙氨酸2.075g，脯氨酸1.775g，天冬氨酸0.625g，天冬酰胺0.1375g，N-乙酰-L-半胱氨酸0.2g(相当于半胱氨酸0.15g)，谷氨酸1.425g，L-鸟氨酸盐酸盐0.415g(相当于L-鸟氨酸0.325g)，丝氨酸0.925g，N-乙酰-L-酪氨酸0.215g(相当于酪氨酸0.175g)]，以及维生素B6 3.0g，10％KCl 5ml，维生素C 2.0g，加入到0.9％氯化钠注射液250ml中。
实施例8
一种药物组合物，其组分为复方氨基酸注射液250ml[含有异亮氨酸2.2g，亮氨酸3.4g，赖氨酸醋酸盐2.65g(相当于赖氨酸1.8775g)，蛋氨酸0.3g，苯丙氨酸0.4g，苏氨酸1.15g，色氨酸0.375g，缬氨酸2.65g，精氨酸2.2g，组氨酸1.175g，甘氨酸1.575g，丙氨酸2.075g，脯氨酸1.775g，天冬氨酸0.625g，天冬酰胺0.1375g，N-乙酰-L-半胱氨酸0.2g(相当于半胱氨酸0.15g)，谷氨酸1.425g，L-鸟氨酸盐酸盐0.415g(相当于L-鸟氨酸0.325g)，丝氨酸0.925g，N-乙酰-L-酪氨酸0.215g(相当于酪氨酸0.175g)]，以及维生素B6 3.0g，10％KCl 5ml，维生素C 2.0g，加入到0.9％氯化钠注射液250ml中。
实施例9
一种药物组合物，其组分为复方氨基酸注射液250ml[含有异亮氨酸2.2g，亮氨酸3.4g，赖氨酸醋酸盐2.65g(相当于赖氨酸1.8775g)，蛋氨酸0.3g，苯丙氨酸0.4g，苏氨酸1.15g，色氨酸0.375g，缬氨酸2.65g，精氨酸2.2g，组氨酸1.175g，甘氨酸1.575g，丙氨酸2.075g，脯氨酸1.775g，天冬氨酸0.625g，天冬酰胺0.1375g，N-乙酰-L-半胱氨酸0.2g(相当于半胱氨酸0.15g)，谷氨酸1.425g，L-鸟氨酸盐酸盐0.415g(相当于L-鸟氨酸0.325g)，丝氨酸0.925g，N-乙酰-L-酪氨酸0.215g(相当于酪氨酸0.175g)]， 以及维生素B6 5.0g，10％KCl 5ml，维生素C 2.0g，胰岛素注射液4u，加入到5％葡萄糖氯化钠注射液250ml中。
实施例10
一种药物组合物，其组分为复方氨基酸注射液500ml[含有异亮氨酸4.4g，亮氨酸6.8g，赖氨酸醋酸盐5.3g(相当于赖氨酸3.775g)，蛋氨酸0.6g，苯丙氨酸0.8g，苏氨酸2.3g，色氨酸0.75g，缬氨酸5.3g，精氨酸4.4g，组氨酸2.35g，甘氨酸3.15g，丙氨酸4.15g，脯氨酸3.55g，天冬氨酸1.25g，天冬酰胺0.275g，N-乙酰-L-半胱氨酸0.4g(相当于半胱氨酸0.3g)，谷氨酸2.85g，L-鸟氨酸盐酸盐0.83g(相当于L-鸟氨酸0.65g)，丝氨酸1.85g，N-乙酰-L-酪氨酸0.43g(相当于酪氨酸0.35g)]，以及维生素B6 3.0g，10％KCl 5ml，加入到0.9％氯化钠注射液250ml中。
实施例11
一种药物组合物，其组分为复方氨基酸注射液500ml[含有异亮氨酸4.4g，亮氨酸6.8g，赖氨酸醋酸盐5.3g(相当于赖氨酸3.775g)，蛋氨酸0.6g，苯丙氨酸0.8g，苏氨酸2.3g，色氨酸0.75g，缬氨酸5.3g，精氨酸4.4g，组氨酸2.35g，甘氨酸3.15g，丙氨酸4.15g，脯氨酸3.55g，天冬氨酸1.25g，天冬酰胺0.275g，N-乙酰-L-半胱氨酸0.4g(相当于半胱氨酸0.3g)，谷氨酸2.85g，L-鸟氨酸盐酸盐0.83g(相当于L-鸟氨酸0.65g)，丝氨酸1.85g，N-乙酰-L-酪氨酸0.43g(相当于酪氨酸0.35g)]，以及维生素B6 5.0g，10％KCl 5ml，维生素C 3.0g，加入到0.9％氯化钠注射液250ml中。
实施例12
一种药物组合物，其组分为复方氨基酸注射液500ml[含有异亮氨酸4.4g，亮氨酸6.8g，赖氨酸醋酸盐5.3g(相当于赖氨酸3.775g)，蛋氨酸0.6g，苯丙氨酸0.8g，苏氨酸2.3g，色氨酸0.75g，缬氨酸5.3g，精氨酸4.4g，组氨酸2.35g，甘氨酸3.15g，丙氨酸4.15g，脯氨酸3.55g，天冬氨酸1.25g，天冬酰胺0.275g，N-乙酰-L-半胱氨酸0.4g(相当于半胱氨酸0.3g)，谷氨酸2.85g，L-鸟氨酸盐酸盐0.83g(相当于L-鸟氨酸0.65g)，丝氨酸1.85g，N-乙酰-L-酪氨酸0.43g(相当于酪氨酸0.35g)]，维生素B6 3.00g，维生素C 2.0g，加入到0.9％氯化钠注射液250ml中。
实施例13
一种药物组合物，其组分为复方氨基酸注射液1000ml(含有：相当于L-鸟氨酸3.5g的L-鸟氨酸盐酸盐，天冬氨酸2.50g，精氨酸8.80g，异亮氨酸8.80g，亮氨酸13.60g，相当于赖氨酸7.51g的赖氨酸醋酸盐，蛋氨酸1.20g，苯丙氨酸1.60g，苏氨酸4.60g，色氨酸1.50g，缬氨酸10.60g，组氨酸4.70g，甘氨酸6.30g，丙氨酸8.30g，脯氨酸7.10g，天冬酰胺0.55g，相当于半胱氨酸0.60g的N-乙酰-L-半胱氨酸，谷氨酸5.70g，丝氨酸3.70g，相当于酪氨酸0.70g的N-乙酰-L-酪氨酸)，以及维生素B6 8.0g和维生素C 3.0g，维生素加入到0.9％氯化钠注射液250ml中。
实施例14
一种药物组合物，其组分为复方氨基酸注射液1000ml(含有：相当于L-鸟氨酸4.5g的L-鸟氨酸盐酸盐，天冬氨酸2.80g，精氨酸8.30g，异亮氨酸6.50g，亮氨酸12.00g，相当于赖氨酸7.51g的赖氨酸醋酸盐，蛋氨酸1.60g，苯丙氨酸1.40g，色氨酸1.80g，缬氨酸10.60g，组氨酸4.80g，甘氨酸6.20g，丙氨酸8.50g，脯氨酸7.10g，天冬酰胺0.55g，谷氨酸5.70g，丝氨酸3.70g，相当于酪氨酸0.70g的N-乙酰-L-酪氨酸)，以及维生素B610g，维生素B1 3mg，维生素B2 3mg，维生素B3 40mg，泛酸8mg，生物素0.4mg，叶酸0.6mg，维生素B12 10μg；维生素C 4.0g。
维生素可直接加入到复方氨基酸注射液中，也可加入到5％葡萄糖氯化钠注射液或0.9％氯化钠注射液250ml中。
实施例15
一种药物组合物，其组分为复方氨基酸注射液1000ml(含有：异亮氨酸8.80g，亮氨酸13.60g，赖氨酸醋酸盐10.60g(相当于赖氨酸7.51g)，蛋氨酸1.20g，苯丙氨酸1.60g，苏氨酸4.60g，色氨酸1.50g，缬氨酸10.60g，精氨酸8.80g，组氨酸4.70g，甘氨酸6.30g，丙氨酸8.30g，脯氨酸7.10g，天冬氨酸2.50g，天冬酰胺0.55g，N-乙酰-L-半胱氨酸0.80g(相当于半胱氨酸0.60g)，谷氨酸5.70g，L-鸟氨酸盐酸盐1.66g(相当于L-鸟氨酸1.30g)，丝氨酸3.70g，N-乙酰-L-酪氨酸0.86g(相当于酪氨酸0.70g))，以及维生素B6 10g。
维生素可直接加入到复方氨基酸注射液中，也可加入到5％葡萄糖氯化钠注射液250ml或0.9％氯化钠注射液250ml中。
实施例16
一种药物组合物，其组分为复方氨基酸注射液1000ml(含有：异亮氨酸8.80g，亮氨酸13.60g，赖氨酸醋酸盐10.60g(相当于赖氨酸7.51g)，蛋氨酸1.20g，苯丙氨酸1.60g，苏氨酸4.60g，色氨酸1.50g，缬氨酸10.60g，精氨酸8.80g，组氨酸4.70g，甘氨酸6.30g，丙氨酸8.30g，脯氨酸7.10g，天冬氨酸2.50g，天冬酰胺0.55g，N-乙酰-L-半胱氨酸0.80g(相当于半胱氨酸0.60g)，谷氨酸5.70g，L-鸟氨酸盐酸盐1.66g(相当于L-鸟氨酸1.30g)，丝氨酸3.70g，N-乙酰-L-酪氨酸0.86g(相当于酪氨酸0.70g))，以及维生素B6 10g和10％KCl 5ml。
维生素可直接加入到复方氨基酸注射液中，也可加入到5％葡萄糖氯化钠注射液250ml或0.9％氯化钠注射液250ml中。
实施例17
一种保健品口服液，其组分为复方氨基酸口服液1000ml(含有：异亮氨酸8.80g，亮氨酸13.60g，赖氨酸醋酸盐10.60g(相当于赖氨酸7.51g)，蛋氨酸1.20g，苯丙氨酸1.60g，苏氨酸4.60g，色氨酸1.50g，缬氨酸10.60g，精氨酸8.80g，组氨酸4.70g，甘氨酸6.30g，丙氨酸8.30g，脯氨酸7.10g，天冬氨酸2.50g，天冬酰胺0.55g，N-乙酰-L-半胱氨酸0.80g(相当于半胱氨酸0.60g)，谷氨酸5.70g，L-鸟氨酸盐酸盐1.66g(相当于L-鸟氨酸1.30g)，丝氨酸3.70g，N-乙酰-L-酪氨酸0.86g(相当于酪氨酸0.70g))，以及维生素B6 10g和维生素C 4.0g。维生素可直接加入到复方氨基酸口服液中，也可以分别包装，一起服用。每日可服用250ml～1000ml。
实施例17
一种保健品片剂，其组分为含有下列复方氨基酸(含有：蛋氨酸0.5g，苯丙氨酸0.5g，苏氨酸1.5g，色氨酸0.5g，缬氨酸3.0g，精氨酸3.0g，甘氨酸1.8g，丙氨酸2.2g，脯氨酸2.0g，天冬氨酸0.8g，天冬酰胺0.5g，谷氨酸1.5g，L-鸟氨酸盐酸盐3.0g，丝氨酸1.2g)，以及维生素B6 3.0g，按片剂常规工艺增加适当辅料制成片剂若干片。
制剂使用说明：以上含复方氨基酸不同剂量(如250ml、500ml、1000ml)的注射液制剂，可根据病人身体耐受情况及体重选用，原则是病人有胃肠道不适症状时选用小 剂量，病人身体耐受较好及体重较重时选用较大剂量，一般情况下采用含复方氨基酸250ml的即可有较好效果。另外，在正规输液治疗后为巩固或维持疗效，可以服用口服制剂。
上述各制剂例中的物质含量通常为病人每日使用的剂量，可根据病情需要适当调整。
二、临床治疗实施例
(一)临床观察统计
本院已收治运动神经元病(肌萎缩侧索硬化)患者48例，临床治疗情况如下：
1、病人入选情况：
1.1一般情况：48例病人，年龄40～77岁，男性多于女性，入院时签署本疗法知情同意书。
1.2诊断标准：
经国内知名医院(如协和医院、上海华山医院、北京大学第三医院等)诊断为运动神经元病或者进一步明确分型为肌萎缩侧索硬化(ALS)者并经我院比照世界神经病学联盟肌萎缩侧索硬化临床诊断标准(EEC，2000)及中国肌萎缩侧索硬化诊断和治疗指南(2012)进行复核确诊，以及在外院未明确诊断经我院根据世界神经病学联盟肌萎缩侧索硬化临床诊断标准(EEC，2000)及中国肌萎缩侧索硬化诊断和治疗指南(2012)诊断的病人，其中临床确认ALS的36人，临床拟诊ALS的8人，临床可能ALS的4人。
1.3、排除标准(以下条件出现任一情况即排除)：
对研究药物过敏者；病人不能合作者；有严重的心、脑血管疾病及肝肾功能不全等疾病；正在使用与试验药物配合配伍禁忌或影响试验药物疗效的药物。
1.4、终止标准：
严重的不良反应；病人的症状恶化，改用其它方法治疗；患者因各种原因要求停药。
2、治疗方案
每日给予下列药物组合物静脉输液(静滴)一次，30天为一个疗程：
0.9％氯化钠注射液250ml+维生素B6 3.0～5.0g+复方氨基酸注射液250～500ml。
必要时分别或同时增加：维生素C 2.0g、10％氯化钾5ml配入上述药物组合物中进行静脉输液。
0.9％氯化钠注射液可根据病人情况替换为5％葡萄糖氯化钠注射液250ml或10％ 葡萄糖注射液250ml。
对吞咽困难、呛咳、或者进食困难的患者可补充葡萄糖注射液及胰岛素注射液，胰岛素注射液的用量按每一个单位(1u)胰岛素比4g葡萄糖计算。
加强病人心理疏导、生活护理和对症治疗。
注：临床采用的复方氨基酸注射液，按1000ml计算含有：异亮氨酸8.80g，亮氨酸13.60g，赖氨酸醋酸盐10.60g(相当于赖氨酸7.51g)，蛋氨酸1.20g，苯丙氨酸1.60g，苏氨酸4.60g，色氨酸1.50g，缬氨酸10.60g，精氨酸8.80g，组氨酸4.70g，甘氨酸6.30g，丙氨酸8.30g，脯氨酸7.10g，天冬氨酸2.50g，天冬酰胺0.55g，N-乙酰-L-半胱氨酸0.80g(相当于半胱氨酸0.60g)，谷氨酸5.70g，L-鸟氨酸盐酸盐1.66g(相当于L-鸟氨酸1.30g)，丝氨酸3.70g，N-乙酰-L-酪氨酸0.86g(相当于酪氨酸0.70g)。
3、疗效观察指标
3.1、无效：经过一个疗程治疗后无作用或症状持续恶化；
3.2、有效：经过一个疗程治疗后患者病情得到控制，不再继续发展或发展速度较治疗前明显降低；
3.3、显效：经过一个疗程或未满一个疗程治疗后患者病情出现好转，出现下列任意一种情形：
3.3.1一个或多个部位肌力恢复，或者增高的肌张力逐步降低；
3.3.2由需呼吸机辅助呼吸变为可脱离呼吸机自由呼吸，或者由长期需呼吸机辅助呼吸变为能间隙采用呼吸机辅助呼吸；
3.3.3呛咳、流涎、吞咽困难、肌肉跳动感、患病部位活动程度等症状明显改善；
3.3.4萎缩的肌肉逐渐生长起来；
3.3.5ALSFRS-R(肌萎缩侧索硬化症功能评分量表)评分数值增加。
注：
ALSFRS-R(肌萎缩侧索硬化症功能评分量表)作为ALS严重程度的评估方法，该量表简便、容易操作、应用广泛，其敏感度、可靠性和稳定性已经得到广泛确认，为国内外常用的评价肌萎缩侧索硬化症病情发展及预后的评分量表，ALSFRS-R由12项组成：1.语言；2.唾液分泌；3.吞咽；4.书写；5.切割食物，使用餐具；6.穿衣及卫生自理；7.在床上翻转及整理被褥；8.行走；9.爬楼梯；10.呼吸困难；11.端坐呼吸；12.呼吸功能不全。每项评分从0分到4分。功能评分从0分(严重受损)到48分(正常)。评分由培训后熟练掌握的专门人员执行。由于ALS为进展性疾病，未能有效治疗情况 下，其ALSFRS-R呈进行性下降，通常6个月下降5～6分，12个月下降10分左右。
4、治疗效果
48例病人经一个月疗程治疗，大部分病人在治疗2周后开始出现效果，一个疗程结束后分析其治疗效果，显示无效4例、有效23例、显效21例。
注：小部分病人使用复方氨基酸注射液的剂量较大时(如500ml/日)会出现恶心等胃部不适症状，减小剂量(如250ml/日)后不适症状消失，体质较弱的病人易出现。
(二)具体病例
本院已收治运动神经元病患者40多例，采用“复方氨基酸联用大剂量维生素B6疗法”治疗均取得了较好的治疗效果，现摘录部分病例如下：
病例1：
患者杨某某，男性，70岁。起病时间为2014年04月，至入院时病程12月。患者以构音障碍及双上肢乏力起病，于2014年04月上海复旦大学附属华山医院诊断为运动神经元病，肌电图(2014-04，华山医院)：运动神经元损害肌电图改变，累及上下肢体、腹直肌、舌肌及斜方肌，首先考虑脊髓前角细胞损害。使用营养神经及口服力鲁肽(1#，bid)治疗，但疗效欠佳。先后于2015年04月28日至2015年05月19日和2015年11月30日至2015年12月10日于武进医院住院接受新疗法治疗。入院时患者进行性四肢肌肉萎缩伴乏力，平地行走困难易跌倒，不能上楼梯，四肢有肉跳感及麻木感；言语含糊，饮水、进食呛咳；呼吸困难，需无创呼吸机持续辅助呼吸。入院前8个月来，体重减轻20.5kg。舌肌萎缩、纤颤；双手骨间肌、四肢肌肉萎缩；双手握力Ⅳ-级，双上肢近端肌力Ⅴ-级，双下肢肌肉Ⅴ-级，巴彬斯基征阳性，腱反射亢进。进一步详细诊断为运动神经元病(肌萎缩侧索硬化症)。患者入院时无法完成肺功能检查。
具体治疗方案：复方氨基酸注射液500ml/日，静滴，1次/日；5％葡萄糖氯化钠注射液250ml+维生素B6 3.0g+维生素C 2.0g，每日1次，静滴。
患者连续用药5天后，呼吸急促、吞咽困难等临床症状明显好转；连续用药15天后，患者口干、消瘦、感觉肉跳、双手麻木、全身肌肉萎缩、乏力、饮水呛咳、气喘等症状都有十分明显的好转，感双上肢近端肌肉和双下肢肌力力量明显增加，可以自由行走。再继续用本疗法治疗1周后，感呛咳、气喘、乏力、视物模糊好转。出院时可脱离无创呼吸机。体重增加2kg。双下肢肌力由Ⅴ-增加为Ⅴ级。2015-12-08可进行肺功能检测，示中度肺功能障碍。
末次出院后一直未再继续使用本疗法治疗。第3次随访得知已患者病情较出院时有 所加重，需有创呼吸机辅助呼吸(2016-10)和插管喂食(2016-10)。说明本疗法虽然能够逆转病情，但如果长时间不维持治疗，病情仍然会继续发展。
PCR检测淋巴细胞分群：
Figure PCTCN2016110316-appb-000001
通过对比治疗前后的淋巴细胞分群检测结果可以发现，患者的免疫功能也得到了改善。
ALSFRS-R评分：
Figure PCTCN2016110316-appb-000002
病例2：
患者刘某，男性，52岁。起病时间为2013年09月，至入院时病程24月。患者以左手指活动障碍起病，于2013年09月复旦大学附属华山医院诊断为运动神经元病，并行肌电图(2016-09，华山医院)检查。于2015年09月14日至2015年09月30日于武进医院诊断为运动神经元病(肌萎缩侧索硬化症)并住院接受本疗法治疗。入院时患者饮水、进食偶有呛咳，讲话费力，含糊；抬头无力，进行性四肢乏力，左手及上肢肌肉明显消瘦，并进行性加重，能平地慢行，易跌倒。舌肌萎缩，纤颤，双手骨间肌，四肢肌肉萎缩，左手握力Ⅰ级，左上肢近端肌力Ⅲ级，右手握力Ⅳ级，右上肢近端肌力Ⅳ级，双下肢肌肉Ⅳ级，巴彬斯基征阳性。
具体治疗方案：复方氨基酸注射液500ml/日，静滴，1次/日；5％葡萄糖氯化钠注射液250ml+维生素B6 3.0g+维生素C 2.0g，每日1次，静滴。
患者入院时只能行走200米，治疗2周后能独立行走3公里，乏力症状好转，左手及上肢肌肉肌力明显增加。出院时左手握力由Ⅰ级增加为Ⅲ级，双下肢肌力由Ⅳ级增加为Ⅴ级。
PCR检测淋巴细胞分群：
Figure PCTCN2016110316-appb-000003
通过对比治疗前后的淋巴细胞分群检测结果可以发现，患者的免疫功能也得到了改善。
ALSFRS-R评分：
Figure PCTCN2016110316-appb-000004
病例3：
患者郝某某，男性，60岁。起病时间为2013年08月，至入院时病程27个月。患者以右臂乏力起病，于北京大学第三医院(2014-06)、中国中医科学院广安门医院(2014-06-22)诊断为运动神经元病(肌萎缩侧索硬化症)，并行肌电图(2014-06-18，北京大学第一附属医院，141515；北京大学第三医院)、肺功能和颈部MRI(2014-06-10，首都医科大学宣武医院，00063326)检查，先后使用神经保护、干细胞移植、中药、针灸推拿等治疗方法，但疗效欠佳。于2015年11月03日至2015年11月18日于武进医院住院接受本疗法治疗。入院时患者进行性双上肢乏力，抬头、耸肩无力，双手小指不能完成并指动作。舌肌纤颤，双上肢、骨间肌及肩部肌肉萎缩；双侧三角肌肌力Ⅲ-级，肱二头肌肌力Ⅲ级，握力稍减弱；双侧肱二头肌反射(+)，双侧肱三头肌反射(+)；双侧Hoffmann征(+)。入院前肌电图示：右母短展肌、双肱二头肌、右胸锁乳突肌呈神经源性损害；左小指展肌、T10脊旁肌轻收缩运动单位电位时限正常波幅增高。肺功能检查(2015-05-15，北京大学第三医院，16724)：通气功能正常，小气道功能正常。
具体治疗方案：复方氨基酸注射液500ml/日，静滴，1次/日；5％葡萄糖氯化钠注射液250ml+维生素B6 5.0g+维生素C 2.0g，每日1次，静滴。
连续治疗10天，右小指可完成并指动作，诉右肩活动度增加。右肘部萎缩肌肉生长了起来。
PCR检测淋巴细胞分群：
Figure PCTCN2016110316-appb-000005
Figure PCTCN2016110316-appb-000006
患者免疫功能变化有好转趋势
ALSFRS-R评分：
Figure PCTCN2016110316-appb-000007
病例4：
患者虞某某，男性，41岁。起病时间为2007年03月，至入院时病程104个月。患者以双腿乏力起病，于上海市中西医结合医院(2007-03-29)、南京医科大学附属常州第二人民医院(2008-03-25)、复旦大学附属中山医院(2008-04-10)和南京脑科医院(2015-05-21)诊断为运动神经元病，并行肌电图(2007-03-30，上海市中西医结合医院，0707431；2008-03-25，常州市第二人民医院，14107)、颅颈MRI(2006-12-29，常州市武进人民医院，08339)检查。曾口服丁苯酞(0.1，tid)、中药治疗，但疗效欠佳。于2015年11月05日至2015年11月19日于武进医院诊断为运动神经元病(肌萎缩侧索硬化症)并住院接受本疗法治疗。入院时患者进行性四肢乏力伴肉跳感，以左侧尤甚。走路不稳，上楼费力；双手麻木，手指不能完成并指动作，双臂不能抬臂过头顶；抬头、耸肩无力；言语不清，饮水呛咳，偶感气喘。舌肌、双手骨间肌及四肢肌肉萎缩，舌肌纤颤；双上肢近端肌力Ⅲ级，双手握力Ⅳ级，双下肢肌力Ⅳ级；肌张力不高；双侧膝反射减弱。入院前肌电图：EMG：上下肢被检肌和腹直肌以及胸锁乳突肌见纤颤正尖波；轻收缩部分被检肌见MUP偏宽大或见巨大电位或波形差；重收缩募集减少。NCV：左侧尺神经深支运动传导CMAP波幅降低；余运动和感觉神经传导速度和波幅正常范围。运动神经F波潜伏期正常范围或未引出。神经源性损害肌电图，累及上下肢和腹直肌以及斜方肌和胸锁乳突肌，舌肌也有轻度慢性损害改变。脊髓前角细胞和舌下神经运动核损害可首先考虑。
具体治疗方案：复方氨基酸注射液500ml/日，静滴，1次/日；5％葡萄糖氯化钠注射液250ml+维生素B6 5.0g+维生素C 2.0g，每日1次，静滴。
治疗2周后乏力症状有所改善，感肩部较前有力，双肩能抬过头部。
PCR检测淋巴细胞分群：
Figure PCTCN2016110316-appb-000008
ALSFRS-R评分：
Figure PCTCN2016110316-appb-000009
病例5：
患者黄某某，男性，52岁。起病时间为2014年03月，至入院时病程20个月。患者以双腿乏力起病，于复旦大学附属华山医院(2014-08-14)、首都医科大学宣武医院(2014-12-22)和北京大学第三医院诊断为运动神经元病(进行性肌萎缩)，并行肌电图(2014-08-14，华山医院，H302091；2014-12-26，宣武医院，50916)、组织活检[2014-12-30，宣武医院，左股四头肌，N12(626955)]、CSF及血清免疫参数分析(2014-08-15，华山医院，20354)、CSF鞘蛋白相关抗体(2014-12-23，宣武医院，41602678)、血清鞘蛋白相关抗体(2014-08-19，华山医院，1952)和血液、尿液毒物分析(2014-12-26，军事医学科学院附属307医院)等多项辅助检查。曾接受多种治疗：辅酶Q10(10mg p.o.tid)、丁苯酞(0.2p.o.bid)、力鲁肽(1#p.o.bid)、大剂量激素冲击及中药治疗，但疗效欠佳。于2015年11月13日至2015年11月29日于武进医院住院接受本疗法治疗。入院时患者进行性四肢乏力，阵发性抽搐伴疼痛。耸肩无力，双下肢完全失去行走能力，有肉跳感。舌肌纤颤、无萎缩；肩部、双下肢肌肉均匀性萎缩。双侧上肢肌力Ⅴ-级，握力稍减弱，双下肢肌力0级，无肌张力，腰肌力量减弱；膝反射(－)；深感觉减弱。入院前肌电图：EMG：上下肢被检肌和腹直肌以及斜方肌和胸锁乳突肌见纤颤正尖波或见束颤电位；轻收缩部分被检肌见MUP偏宽大或见巨大电位伴或补办多相电位和不规则波增多；重收缩募集减少。NCV：双侧肺总神经运动传导CMAP 波幅降低；余运动和感觉神经传导速度和波幅正常范围。运动神经F波潜伏期正常范围或未引出。神经源性损害肌电改变，累及上下肢肌和腹直肌以及斜方肌和胸锁乳突肌。脊髓前角细胞损害可首先考虑。
具体治疗方案：复方氨基酸注射液500ml/日，静滴，1次/日；5％葡萄糖氯化钠注射液250ml+维生素B6 5.0g+维生素C 2.0g，每日1次，静滴。
治疗10天后已经能够自行站立6分钟了，双下肢肌肉的肌力和肌肉营养比较治疗前明显改善。足部肌肉有收缩动作，膝跳反射减弱，双下肢肌张力较入院时增加。
PCR检测淋巴细胞分群：
Figure PCTCN2016110316-appb-000010
通过对比治疗前后的淋巴细胞分群检测结果可以发现，患者的免疫功能也得到了改善。
ALSFRS-R评分：
Figure PCTCN2016110316-appb-000011
病例6：
患者黄某某，男性，50岁。起病时间为2014年04月，至入院时病程29个月。患者以右腿乏力起病，于同济大学附属东方医院(2016-04-05)、上海中医药大学附属曙光医院(2016-06-17)和上海交通大学医学院附属新华医院(2016-04-22)诊断为运动神经元病(下运动神经元综合征，脊肌萎缩症可能)，并行肌电图(2016-04-05，同济大学附属东方医院，147591；2016-04-22，上海交通大学医学院附属新华医院,，40621；2016-06-17，上海中医药大学附属曙光医院，24172；2016-04-25，上海交通大学医学院附属新华医院，40621)、颅颈胸腰MRI(2016-04-07，同济大学附属东方医院，M13155250、M13155249、M13155247、M13155248)检查。曾口服多种药物(泛癸利酮胶囊，2#p.o.tid；维生素E-10胶丸，1#p.o.tid；维生素B1片，1#p.o.tid；甲钴胺片，1#p.o.tid)及中药治疗，但疗效不理想。于2016年09月29日至2016年10月27日于武进医院住院接受本疗法治疗。入院时患者 进行性四肢乏力伴活动欠灵活，双下肢为重，双腿偶有肉跳感，爬楼梯困难，易摔到。双下肢能床上水平抬高10cm。左侧髂腰肌肌力Ⅴ-级，臀大肌肌力Ⅴ-级，双侧股四头肌、胫前肌及小腿后肌群肌力Ⅳ级。肌张力稍降低。咽反射(+)，双侧肱二头肌减反射(++)，双侧膝反射(+)，踝反射(+)。神经源性疾病肌电图(上海中医药大学附属曙光医院)：累及四肢检肌、腹直肌、脊旁肌，均有失神经改变；斜方肌有***电位延长，并有巨大电位。考虑MND可能。
具体治疗方案：复方氨基酸注射液250ml+0.9％氯化钠注射液250ml+维生素B6 5.0g，静脉滴注，每日一次。
住院治疗4周后，患者感下肢乏力有所缓解，出院时双下肢能床上水平抬高30cm(较入院时增加20cm)。
PCR检测淋巴细胞分群：
Figure PCTCN2016110316-appb-000012
血肌红蛋白测定：
Figure PCTCN2016110316-appb-000013
ALSFRS-R评分：
Figure PCTCN2016110316-appb-000014
病例7：
患者朱某某，男性，50岁。起病时间为2015年08月，至入院时病程13个月。患者以左腿乏力及左足趾活动障碍起病，于苏州大学附属第一医院(2015-09-24)和浙江省中医院(2016-03-01)诊断为运动神经元病，并行肌电图(2015-09-24，苏州大学一 附院，9755；2016-03-01，浙江省中医药，160367-05705；2016-05-30，苏州大学一附院，11332；)检查。曾口服多种药物[甲钴胺，0.5mg p.o.tid；呋喃硫胺，25mg p.o.tid；强的松，20mg p.o.qd(每5天减1片)；银杏内酯，1#p.o.tid]进行治疗，但疗效不理想。于2016年09月28日至2016年10月28日于武进医院诊断为运动神经元病(肌萎缩侧索硬化症)并住院接受本疗法治疗。入院时四肢乏力明显伴肉跳感，双下肢为甚，行走困难易跌倒，左足趾明显强制性过伸，活动受限。双侧肱二头肌萎缩，双侧股四头肌、胫骨前肌及小腿后侧肌群萎缩。髂腰肌肌力Ⅳ级，双侧股四头肌肌力Ⅳ级，左侧小腿后侧肌群肌力Ⅲ级，右侧小腿后侧肌群肌力Ⅳ级，双侧胫前肌肌力Ⅲ级。右足跖曲、背曲无力。四肢肌张力低，左足趾肌张力增高。肱二头肌反射消失。患者胞妹同病。入院前肌电图示：1.右腓总神经运动神经传导诱发电位波幅降低；2.双胫神经运动神经传导远端潜伏期延长，诱发电位波幅降低；3.左腓总神经运动神经传导呈微小运动反应；4.右小指展肌静息下可见束颤电位，轻收缩呈正常大小MUP，大力收缩呈近干扰相；5.左股四头肌、右胫前肌、左胫前肌肌电图检查呈神经源性肌电改变；6.右侧股四头肌静息下可见自发电位发放，轻收缩见部分宽大MUP。
具体治疗方案：复方氨基酸注射液250ml+5％葡萄糖氯化钠注射液250ml+维生素B6 5.0g+维生素C 2.0g+胰岛素4U+10％KCl 5ml，静脉滴注，每日一次。
经过规律本疗法治疗30天后，患者四肢乏力症状缓解，左足趾强制性过伸消失。体重较入院时增加1kg。左足肌张力增高现象明显缓解，活动灵敏度增加。出院本院复查肌电图示：1.上下肢被检肌肉见纤颤正尖波；2.轻收缩双侧第一背侧骨间肌，右侧胫前肌、桡侧腕屈肌MUP偏宽大；3.双侧腓内肌、右侧股内肌MUP偏宽；4.右侧股内肌，左侧胫前肌MUP波形差；5.双侧正中神经运动传导远端潜伏期延长；6.左侧正中神经、双侧腓总神经及左侧胫神经运动传导CMAP波幅降低；7.左侧腓总神经运动传导速度减慢；8.右侧尺神经感觉传导SANP波幅降低。对比出入院肌电图，原仅呈现微小运动反应的左腓总神经已能测出相应运动电位波，大部分受累神经传导波幅增高。
PCR检测淋巴细胞分群：
Figure PCTCN2016110316-appb-000015
Figure PCTCN2016110316-appb-000016
肌红蛋白测定：
Figure PCTCN2016110316-appb-000017
ALSFRS-R评分：
Figure PCTCN2016110316-appb-000018
病例8：
患者徐某某，男性，66岁。起病时间为2015年05月，至入院时病程17个月。患者以构音障碍起病，于复旦大学附属华山医院(2016-03-28)诊断为运动神经元病。行肌电图(2016-02-16，江苏省人民医院，C20160181；2016-03-28，复旦大学附属华山医院，58927)、颅颈腰骶MRI(2015-06-09，鼓楼医院，颅MRI+MRA；2015-09，东南大学附属中大医院，颅MRI+MRA，颈、胸、腰骶，964151XGT)及肺功能(2016-02-04，江苏省中医院，KSXUGT16020402)检查。曾口服力鲁肽治疗，但疗效欠佳。于2016年10月17日至2016年11月13日于武进医院诊断为运动神经元病(肌萎缩侧索硬化症)并住院接受本疗法治疗。入院时言语含糊伴流涎，吞咽困难，饮水、进食呛咳，四肢乏力以左侧尤甚，左下肢肉跳感，行走不稳，以上症状进行性加重。舌肌萎缩明显，纤颤；左手握力Ⅳ级，左上肢近端肌力Ⅳ级，双侧胫前肌肌力Ⅳ级，双足跖曲、背曲弱；四肢肌张力稍减低；肱二头肌反射消失。入院前肌电图：EMG:左舌肌见纤颤，右舌肌未查；左侧第一背侧骨间肌、桡侧腕屈肌、舌肌，右侧桡侧腕屈肌见正锐波；右侧胸锁乳突肌见束颤波；上下肢部分被检肌见***电位延长，轻收缩见MUP偏宽大伴或不伴多相电位和不规则波增多；冲收缩募集减少。NCV：被检运动和感觉神经传导速度和波幅正常范围。运动神经F波潜伏期正常范围。Blink：双侧眶上切迹刺激眼轮匝肌记录R1和R2潜伏期正常范围。神经源性损害肌电改变，累及舌肌为主，上肢部分肌和胸锁乳突肌也有轻度累及。
具体治疗方案：复方氨基酸注射液300ml+0.9％氯化钠注射液250ml+维生素B6 3.0g+维生素C 2.0g，静脉滴注，每日一次。
经过规律本疗法治疗30天后，患者述四肢乏力明显改善，左下肢活动灵活度增加；流涎减少。出院复查肌电图：EMG：双侧舌肌见纤颤波；右侧胫前肌及双侧舌肌见正锐波；轻收缩部分被检肌见MUP偏宽或部分偏宽大；重收缩募集减少。NUV：被检运动和感觉神经传导速度和波幅正常范围。神经源性损害肌电改变，累及舌肌为主，上下肢和斜方肌也有轻度累及。脊髓前角细胞和舌下神经运动核损害可首先考虑。
PCR检测淋巴细胞分群：
Figure PCTCN2016110316-appb-000019
血肌红蛋白测定：
Figure PCTCN2016110316-appb-000020
ALSFRS-R评分：
Figure PCTCN2016110316-appb-000021
病例9：
患者王某某，男性，53岁。起病时间为2015年09月，至入院时病程13个月。患者以右手指乏力起病，于东南大学附属中大医院(2016-10-11)诊断为运动神经元病。行肌电图(2016-10-10，东南大学附属中大医院，000875)和颅颈MRI(2016-02-2，天长市中医院)检查。曾予口服力鲁肽(1#p.o.bid)及改善循环、营养神经等治疗，但疗效欠佳且病情迅速发展。于2016年10月12日至2016年11月08日于武进医院诊断为运动神经元病(肌萎缩侧索硬化症)并住院接受本疗法治疗。入院时进行性四肢乏力，以左侧尤甚，行走缓慢且易跌倒，上肢不能梳头及提重物，肩部上抬无力伴肉跳感；言语较含糊。双手骨间肌萎缩、畸形，双侧肱二头肌萎缩；右手握力Ⅰ～Ⅱ级，左手握力 Ⅲ级，左上肢近端肌力Ⅰ级，右上肢近端肌力Ⅳ级，髂腰肌肌力Ⅳ级，双侧小腿后侧肌群肌力Ⅳ级，双侧胫前肌肌力Ⅳ级，双足跖曲、背曲稍弱；四肢肌张力低；肱二头肌反射消失。入院前肌电图(2016-10-10，东南大学附属中大医院)：EMG：右侧三角肌、右侧胫前肌安静时可见大量自发电位，小力收缩运动单位电位时限增宽，大力收缩募集呈单纯相。左侧胸锁乳突肌小力收缩运动单位电位时限增宽，搭理收缩募集减少。右侧T11、T10安静时可见大量自发电位。NCV：1.右侧正中神经运动末端潜伏期正常高限，传导速度正常，CMAP波幅降低，F波未引出；感觉传导速度正常，SNAP波幅正常。2.右侧尺神经运动末端潜伏期延长，传导速度正常，CMAP波幅降低，F波未引出；感觉传导速度正常，SNAP波幅正常。广泛神经源性损害。
具体治疗方案：复方氨基酸注射液250ml+0.9％氯化钠注射液250ml+维生素B6 3.0g+维生素C 2.0g+10％KCl 10ml，静脉滴注，每日一次。
经过规律本疗法治疗20余天后，患者述感双下肢乏力好转，行走较入院时有力。余好转不明显，但病程进展速度显著下降，病情得到一定程度的控制。出院时肌电图(2016-11-04)：EMG：上下肢被检肌和舌肌见纤颤正尖波；亲手所部分被检肌见MUP偏宽大或部分宽大；重收缩募集减少。NCV：右侧郑重神经和尺神经传导CMAP波幅降低；余运动和感觉神经传导速度和波幅正常范围。神经源性损害肌电改变，累及上下肢肌和舌肌，斜方肌也有轻度累及。脊髓前角细胞和舌下神经运动核损害可首先考虑。
PCR检测淋巴细胞分群：
Figure PCTCN2016110316-appb-000022
血肌红蛋白测定：
Figure PCTCN2016110316-appb-000023
ALSFRS-R评分：
Figure PCTCN2016110316-appb-000024
病例10：
患者田某，女性，51岁。起病时间为2012年10月，至入院时病程39个月。患者以双下肢乏力起病，于首都医科大学宣武医院(2014-04-16，病历号：605437)、北京大学第三医院(2014-11-02，住院号：4770669)诊断为意义未确定的单克隆丙球蛋白病；肌肉病。于多家医疗机构诊疗期间进行多项相关检查，包括颈腰MRI(2014-02-25，空军总医院)；血清蛋白电泳、免疫球蛋白定量、免疫固定电泳、尿本周氏蛋白、大腿肌肉MRI、左股四头肌肌肉活检、肌电图、氨基酸及肉碱谱检查、尿有机酸谱、血尿毒物分析等(2014-03-26至2014-04-10宣武医院住院期间)；PET/CT(2014-04-21，解放军总医院)；免疫球蛋白固定电泳、肌电图、右股二头肌肌肉活检、骨髓活检；TB淋巴细胞亚群测定、CA125、本周氏蛋白定性、癌胚抗原、风湿三项、免疫七项、脑脊液常规、肿瘤特异性生长因子、全身+局部骨成像、白血病/淋巴瘤免疫分型等(2014-11-02至2014-11-06北京大学第三医院住院期间)；单基因遗传病基因检测报告(2015-03-10，深圳华大临床检验中心)；KAP+LAM(2015-05-22，北京协和医院)。曾接受激素治疗、B族维生素、中药、干细胞移植、营养神经等治疗，但疗效欠佳。于2016年01月18日至2016年01月30日于武进医院诊断为运动神经元病(进行性肌萎缩)并住院接受本疗法治疗。患者入院时进行性加重的四肢乏力伴肌肉明显萎缩，双下肢不能独立行走，偶有大腿肌肉跳动感，咳嗽咳痰力量减弱，抬头耸肩无力，呼吸困难，需无创呼吸机间断性辅助呼吸。双侧肱二头肌萎缩，双手握力Ⅴ级，双上肢近端肌力Ⅰ级。双下肢无浮肿，双大腿股四头肌肌肉萎缩明显。髂腰肌Ⅱ级，双侧股四头肌肌力0级，双侧小腿后侧肌群肌力Ⅱ级。双侧侧胫前肌肌力Ⅱ级。左侧踇背伸肌肌力Ⅱ级，右侧踇背伸肌肌力Ⅱ级，肌张力低。痛温觉存在，腱反射未引出。入院前两次肌电图均为肌源性损害。左股四头肌病例活检(2014-04-01，首都医科大学宣武医院)示：神经源性损害。
具体治疗方案：复方氨基酸注射液500ml，静脉滴注，每日一次；0.9％氯化钠注射液500ml+维生素B6 5.0g，静脉滴注，每日一次。
经过规律本疗法治疗后，乏力症状稍有好转，颈部及四肢肌力稍增加，双侧斜方肌及臀大肌萎缩明显好转，肌肉较入院时饱满。入院治疗10天后能搀扶后站立及行走， 可以独立行走(拖行)约5米。双侧股四头肌肌力由0级增加为Ⅰ级。
PCR检测淋巴细胞分群：
Figure PCTCN2016110316-appb-000025
ALSFRS-R评分：
Figure PCTCN2016110316-appb-000026
病例11：
患者陶某某，男性，64岁。起病时间为2014年03月，至入院时病程31个月。患者以构音障碍、吞咽困难起病，于复旦大学附属华山医院(2015-06-26)、北京协和医院(2016-04-25)和浙江省台州医院(2015-06-18)诊断为运动神经元病(肌萎缩侧索硬化症)，行肌电图(2015-06-18，浙江省台州医院)。曾予口服力鲁肽(1#p.o.bid，自2015年04起持续口服)、中药等治疗，但疗效欠佳。于2016年10月18日至2016年12月05日于武进医院住院接受本疗法治疗。入院时进行性言语含糊、四肢乏力，耸肩、抬头无力，伴明显流涎及吞咽困难。体重下降约10kg。四肢及舌肌肌肉萎缩；左上肢近端肌力Ⅳ级，双侧胫前肌肌力Ⅳ级；跖曲、背曲弱；四肢肌张力稍低；肱二头肌腱反射(-)。入院前肌电图示广泛神经源性损害。
具体治疗方案：复方氨基酸注射液300ml+维生素B6 3.0g+维生素C 2.0g+0.9％氯化钠注射液250ml，静脉滴注，每日一次；消旋山莨菪碱片10mg(口服)。
经过规律本疗法治疗后，患者感流涎明显减少，吞咽困难较入院时明显改善，全身乏力症状缓解。出院时复查肌电图：EMG：双上肢部分被检肌和斜方肌见纤颤正尖波；轻收缩部分肌见MUP偏宽大或部分偏宽大；冲收缩募集减少。NCV：右侧正中神经和尺神经运动传导CMAP波幅降低；余运动和感觉神经传导速度和波幅正常范围。神经源性损害肌电改变，累计双上肢和斜方肌以及胸锁乳突肌，双下肢肌也有轻度累及。脊 髓前角细胞损害可首先考虑。
PCR检测淋巴细胞分群：
Figure PCTCN2016110316-appb-000027
血肌红蛋白测定：
Figure PCTCN2016110316-appb-000028
ALSFRS-R评分：
Figure PCTCN2016110316-appb-000029
病例12：
患者朱某某，男性，77岁。起病时间为2015年11月，至入院时病程8个月。患者以构音障碍、舌活动欠灵活起病，于南京医科大学附属常州市第二人民医院(2016-05)诊断为运动神经元病，行肌电图(2016-05，常州市第二人民医院；2016-06-06，上海交通大学医学院附属仁济医院，2042)和颅颈MRI(2016-05，常州市第二人民医院)检查。曾予口服力鲁肽(1#p.o.bid)、维生素B1(1#p.o.tid)、维生素E(1#p.o.tid)等治疗，但疗效欠佳。于2016年07月28日至2016年08月25日于武进医院诊断为运动神经元病(进行性延髓麻痹)并住院接受本疗法治疗。入院时患者入院时言语不清，伴明显流涎。2011年脑梗后遗留左侧上下肢麻木和行走拖行及活动障碍。舌肌萎缩，纤颤；左小腿后侧肌群肌力Ⅳ级，四肢肌张力稍低；咽反射迟钝。入院前肌电图：EMG：所检小部分肌肉放松时出现不同程度正尖、纤颤电位，重收缩运动单位电位略减小。CV：双侧腓神经MCV、SCV波幅降低，余所检神经SCV、MCV均在正常范围。RNS：分别刺激左右面神经、右尺神经、右腓神经、眼轮匝肌、小指展肌、趾短伸肌记录为明显特征性改变。
具体治疗方法：复方氨基酸注射液250ml，静脉滴注，每日一次；0.9％氯化钠注射液250ml+维生素B6 3.0g+10％KCl 5ml，静脉滴注，每日一次。
经过规律本疗法治疗后，患者感流涎明显减少，四肢乏力症状好转。
PCR检测淋巴细胞分群：
Figure PCTCN2016110316-appb-000030
ALSFRS-R评分：
Figure PCTCN2016110316-appb-000031

Claims (13)

  1. 一种用于治疗运动神经元病的组合物，其特征是每单位该组合物中含有下列用量比例关系的物质：
    L-鸟氨酸0.3～8g或者相当于L-鸟氨酸含量为0.3～8g的L-鸟氨酸盐，天冬氨酸0.5～5g，维生素B62～20g；
    优选L-鸟氨酸0.325～8g或者相当于L-鸟氨酸含量为0.325～8g的L-鸟氨酸盐，天冬氨酸0.625～5g，维生素B63～20g；
    进一步优选L-鸟氨酸0.5～8g或者相当于L-鸟氨酸含量为0.5～8g的L-鸟氨酸盐，天冬氨酸1～5g，维生素B66～20g；
    或者
    进一步优选L-鸟氨酸0.325～0.65g或者相当于L-鸟氨酸含量为0.325～0.65g的L-鸟氨酸盐，天冬氨酸0.625～1.25g，维生素B63～10g。
  2. 根据权利要求1所述的组合物，其特征在于每单位该组合物中还含有下列物质中的任意一种或多种：精氨酸，异亮氨酸，亮氨酸，赖氨酸，蛋氨酸，苯丙氨酸，苏氨酸，色氨酸，缬氨酸，组氨酸，甘氨酸，丙氨酸，脯氨酸，天冬酰胺，半胱氨酸，谷氨酸，丝氨酸，酪氨酸，维生素B1，维生素B2，维生素B3，泛酸，生物素，叶酸，维生素B12，维生素C，KCl；
    上述氨基酸可以采用氨基酸的各种可溶性盐或者其衍生物替代。
  3. 根据权利要求2所述的组合物，其特征在于赖氨酸采用赖氨酸醋酸盐替代，半胱氨酸采用N-乙酰-L-半胱氨酸替代，酪氨酸采用N-乙酰-L-酪氨酸替代；所述任意一种或多种物质的用量对应以下用量比例关系：
    各氨基酸的用量比例关系分别是：精氨酸2.0～10g，异亮氨酸2.0～10g，亮氨酸3.0～15g，相当于赖氨酸含量为1.5～10g的赖氨酸醋酸盐，蛋氨酸0.2～3g，苯丙氨酸0.3～3g，苏氨酸1.0～10g，色氨酸0.3～3g，缬氨酸2.5～15g，组氨酸1.0～8g，甘氨酸1.5～8g，丙氨酸2.0～10g，脯氨酸1.5～8g，天冬酰胺0.1～3g，相当于半胱氨酸含量为0.1～3g的N-乙酰-L-半胱氨酸，谷氨酸1.0～10g，丝氨酸0.5～5g，相当于酪氨酸含量为0.1～3g的N-乙酰-L-酪氨酸；
    维生素的用量比例关系分别是：维生素B11.0～4.0mg，维生素B21.0～4.0mg，维生素B310～40mg，泛酸3.0～10mg，生物素0.1～0.4mg，叶酸0.1～0.8mg，维生素B12 2.0～12μg；维生素C1.0-6.0g；
    KCl的用量为10％KCl5～10ml；
    优选：
    各氨基酸的用量比例关系分别是：精氨酸2.2～4.4g，异亮氨酸2.2～4.4g，亮氨酸3.4～6.8g，相当于赖氨酸含量为1.8775～3.755g的赖氨酸醋酸盐，蛋氨酸0.3～0.6g，苯丙氨酸0.4～0.8g，苏氨酸1.15～2.3g，色氨酸0.375～0.75g，缬氨酸2.65～5.3g，组氨酸1.175～2.35g，甘氨酸1.575～3.15g，丙氨酸2.075～4.15g，脯氨酸1.775～3.55g，天冬酰胺0.1375～0.275g，相当于半胱氨酸含量为0.15～0.3g的N-乙酰-L-半胱氨酸，谷氨酸1.425～2.85g，丝氨酸0.925～1.85g，相当于酪氨酸含量为0.175～0.35g的N-乙酰-L-酪氨酸；
    维生素的用量比例关系分别是：维生素B11.0～4.0mg，维生素B21.0～4.0mg，维生素B310～40mg，泛酸3.0～10mg，生物素0.1～0.4mg，叶酸0.1～0.8mg，维生素B122.0～12μg；维生素C1.0-6.0g；
    KCl的用量为10％KCl5～10ml；
    或者优选：
    各氨基酸的用量比例关系分别是：精氨酸3.0～10g，异亮氨酸3.0～10g，亮氨酸5.0～15g，相当于赖氨酸含量为3.0～10g的赖氨酸醋酸盐，蛋氨酸0.5～3g，苯丙氨酸0.5～3g，苏氨酸3.0～10g，色氨酸0.5～3.0g，缬氨酸5.0～15g，组氨酸3.0～8.0g，甘氨酸3.0～8.0g，丙氨酸3.0～10g，脯氨酸3.0～8.0g，天冬酰胺0.1～3.0g，相当于半胱氨酸含量为0.1～3.0g的N-乙酰-L-半胱氨酸，谷氨酸3.0～10g，丝氨酸0.5～5.0g，相当于酪氨酸含量为0.1～3g的N-乙酰-L-酪氨酸；
    维生素的用量比例关系分别是：维生素B12.0～4.0mg，维生素B22.0～4.0mg，维生素B320～40mg，泛酸6.0～10mg，生物素0.2～0.4mg，叶酸0.2～0.8mg，维生素B124.0～12μg；维生素C2.0-6.0g。
  4. 根据权利要求3所述的组合物，其特征在于每单位该组合物中含有下列用量比例关系的物质：
    异亮氨酸2.2g，亮氨酸3.4g，赖氨酸醋酸盐2.65g(相当于赖氨酸1.8775g)，蛋氨酸0.3g，苯丙氨酸0.4g，苏氨酸1.15g，色氨酸0.375g，缬氨酸2.65g，精氨酸2.2g，组氨酸1.175g，甘氨酸1.575g，丙氨酸2.075g，脯氨酸1.775g，天冬氨酸0.625g，天冬酰胺0.1375g，N-乙酰-L-半胱氨酸0.2g(相当于半胱氨酸0.15g)，谷氨酸0或1.425g， L-鸟氨酸盐酸盐0.415g(相当于L-鸟氨酸0.325g)，丝氨酸0.925g，N-乙酰-L-酪氨酸0.215g(相当于酪氨酸0.175g)，维生素B63.0～5.0g，10％KCl0或5～10ml，维生素C0或2.0～6.0g；或者
    异亮氨酸4.4g，亮氨酸6.8g，赖氨酸醋酸盐5.3g(相当于赖氨酸3.775g)，蛋氨酸0.6g，苯丙氨酸0.8g，苏氨酸2.3g，色氨酸0.75g，缬氨酸5.3g，精氨酸4.4g，组氨酸2.35g，甘氨酸3.15g，丙氨酸4.15g，脯氨酸3.55g，天冬氨酸1.25g，天冬酰胺0.275g，N-乙酰-L-半胱氨酸0.4g(相当于半胱氨酸0.3g)，谷氨酸0或2.85g，L-鸟氨酸盐酸盐0.83g(相当于L-鸟氨酸0.65g)，丝氨酸1.85g，N-乙酰-L-酪氨酸0.43g(相当于酪氨酸0.35g)，维生素B63.0～10g，10％KCl0或5～10ml，维生素C0或2.0～6.0g。
  5. 根据权利要求1-4所述的任一组合物，其特征在于该组合物还含有适量的5％葡萄糖氯化钠注射液或0.9％氯化钠注射液或10％葡萄糖注射液。
  6. 根据权利要求5所述的任一组合物，其特征在于含有葡萄糖的该组合物还可加入胰岛素，胰岛素的用量为每一个单位(1u)胰岛素比3～5g葡萄糖，优选每一个单位(1u)胰岛素比4g葡萄糖。
  7. 根据权利要求5所述的任一组合物，其特征在于该组合物的具体配方为：
    0.9％氯化钠注射液250ml+维生素B63.0g或5.0g+复方氨基酸注射液250ml或500ml；或者
    0.9％氯化钠注射液250ml+维生素B63.0g或5.0g+复方氨基酸注射液250ml或500ml+维生素C2.0g；或者
    0.9％氯化钠注射液250ml+维生素B63.0g或5.0g+复方氨基酸注射液250ml或500ml+10％氯化钾5ml；或者
    0.9％氯化钠注射液250ml+维生素B63.0g或5.0g+复方氨基酸注射液250ml或500ml+维生素C2.0g+10％氯化钾5ml；或者
    5％葡萄糖氯化钠注射液250ml+胰岛素注射液4u+维生素B63.0g或5.0g+维生素C2.0g+10％氯化钾5ml+复方氨基酸注射液250ml；或者
    10％葡萄糖注射液250ml+胰岛素注射液8u+维生素B63.0g或5.0g+维生素C2.0g+10％氯化钾5ml+复方氨基酸注射液250ml；
    其中：
    所述复方氨基酸注射液，按1000ml计算含有：异亮氨酸8.80g，亮氨酸13.60g，赖氨酸醋酸盐10.60g(相当于赖氨酸7.51g)，蛋氨酸1.20g，苯丙氨酸1.60g，苏氨酸 4.60g，色氨酸1.50g，缬氨酸10.60g，精氨酸8.80g，组氨酸4.70g，甘氨酸6.30g，丙氨酸8.30g，脯氨酸7.10g，天冬氨酸2.50g，天冬酰胺0.55g，N-乙酰-L-半胱氨酸0.80g(相当于半胱氨酸0.60g)，谷氨酸5.70g，L-鸟氨酸盐酸盐1.66g(相当于L-鸟氨酸1.30g)，丝氨酸3.70g，N-乙酰-L-酪氨酸0.86g(相当于酪氨酸0.70g)。
  8. 根据权利要求1-7所述的任一组合物，其特征在于该组合物的剂型为药学上允许的任意剂型或保健品允许的任意剂型；该组合物的剂型优选为注射剂、口服液、片剂、颗粒剂、胶囊剂、冲剂。
  9. 权利要求1-7所述的任一组合物在制备治疗运动神经元病的药物或保健品中的应用。
  10. 根据权利要求9所述的应用，其特征在于所述运动神经元病包括肌萎缩侧索硬化、脊肌萎缩症、原发性侧索硬化、进行性延髓麻痹，优选肌萎缩侧索硬化。
  11. 一种治疗运动神经元病的方法，其特征在于该方法采用注射或口服的方式给予患者权利要求1-7所述的任一组合物；所述注射方式优选静脉注射。
  12. 根据权利要求11所述的方法，其特征在于每个疗程为采用注射或口服的方式给予患者权利要求1-7所述的任一组合物10-40天，优选15-30天；一个疗程结束后，可以根据治疗需要在休息适当时间后继续进行下一个疗程或者不进行下一个疗程
  13. 根据权利要求12所述的方法，其特征在于对于吞咽困难、呛咳、或者进食困难的患者可补充葡萄糖注射液及胰岛素。
PCT/CN2016/110316 2015-12-21 2016-12-16 一种用于治疗运动神经元病的组合物及其用途 WO2017107863A1 (zh)

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